C-Type lectin receptors as key modulators of intestinal inflammation: insights into IBD pathogenesis and therapy

Abstract

This review focuses on the role of C-type lectin receptors (CLRs) in inflammatory bowel disease (IBD). It outlines their classification, structural features, and functional mechanisms within intestinal immunity. The article comprehensively examines recent advances in understanding the contributions of specific CLRs—including Dectin-1, Mincle, Dectin-3, and the mannose receptor (MR/CD206)—to IBD pathogenesis, particularly their functions in microbial recognition, immune cell activation, and the regulation of inflammatory responses. Finally, the review addresses current research challenges and future directions, with the aim of providing deeper insights into disease mechanisms and facilitating the development of novel CLR-targeted therapies.

This review examines CLRs (e.g., Dectin-1, Mincle) in IBD, covering their roles in gut microbiota recognition, immune activation, and inflammation regulation..

Introduction

Inflammatory bowel disease (IBD) is a chronic, relapsing intestinal inflammatory disorder, primarily encompassing Crohn’s disease (CD) and ulcerative colitis (UC), characterized by non-infectious chronic inflammation. The condition of this disease is prone to relapse, which has a significant negative impact on the quality of life of patients. Moreover, it remains an incurable disease globally. With the continuous advancement of modernization and industrialization, the incidence trend of IBD has shown new changes. Previously, this disease was more common in European and American countries, but in recent years, the incidence of IBD in developing countries such as Asia, South America, and Africa has been increasing year by year, evolving into a global disease and posing a heavy burden on the global medical system (Kaplan and Windsor 2021). In 2019, there were approximately 4.9 million IBD patients worldwide, with China and the United States having the largest number of patients, with 911 405 and 762 890 cases, respectively (R. Wang et al. 2023). In 2019, there were 51 500 new cases of IBD in China and 4676 deaths (Y. Zhang et al. 2022b).

The pathogenesis of IBD is complex, involving multiple interactions among genetic susceptibility, environmental exposure, intestinal microbiota dysbiosis, and abnormal immune system activation (Geremia et al. 2014, Larabi et al. 2020, Zhang and Li 2014). It is worth noting that the intestine, as the largest immune organ in the human body, highly depends on the precise balance between immune tolerance to the commensal microbiota and defensive responses to pathogens for maintaining homeostasis. Once this balance is disrupted, excessive immune activation will lead to a vicious cycle of intestinal barrier destruction and chronic inflammation. In recent years, pattern recognition receptors (PRRs), which play a key regulatory role in this process, have gradually become the focus of research. PRRs can initiate downstream signal transduction cascades by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), thus playing a central role in the initiation and regulation of immune responses (Fukata and Arditi 2013, Walsh et al. 2013, Zhou et al. 2018). Among numerous PRRs, C-type lectin receptors (CLRs) have attracted increasing attention due to their unique glycan ligand recognition ability and bidirectional regulatory characteristics in immune homeostasis, showing unique biological significance in the pathogenesis of IBD.

Discovery and functional diversity of C-type lectin receptors

C-type lectins (CTLs), as a superfamily of proteins containing one or more C-type lectin-like domains (CTLDs), can be subdivided into two main categories according to the differences in their subcellular localization: secretory and membrane-bound types (Brown et al. 2018). Among them, membrane-bound CTLs are also known as CLRs (Brown et al. 2018). The basic structural feature of CLRs is the presence of one or more carbohydrate recognition domains (CRDs), which can specifically recognize various ligands in a Ca²⁺-dependent manner (Monteiro and Lepenies 2017, Fischer et al. 2022). There are differences in the structure and function of CRDs among different types of CLRs, enabling them to recognize different types of ligands. In addition, CLRs also have a transmembrane region and a cytoplasmic region. The transmembrane region is responsible for anchoring the receptor on the cell membrane, while the cytoplasmic region participates in signal transduction. Some CLRs' cytoplasmic regions contain immunoreceptor tyrosine-based activation motifs (ITAMs), which can recruit corresponding signal molecules after ligand binding, thereby initiating downstream signaling pathways (Brown et al. 2018).

The study of CLRs originated in the late 20th century. In 1995, the identification of DEC-205 (CD205) revealed a highly efficient endocytic receptor on dendritic cells capable of antigen uptake and presentation to T cells, providing initial evidence that CLRs may participate in the initiation of immune responses (Jiang et al. 1995). Subsequently, the functional characterization of DC-SIGN further established that a class of CLRs could directly recognize mannosylated carbohydrate structures on pathogen surfaces—such as those of HIV and mycobacteria—and activate the Ras-Raf1 signaling pathway, thereby molecularly defining CLRs as PRRs (Geijtenbeek et al. 2000a,b, Gringhuis et al. 2007). These foundational observations established CLRs as critical bridges linking pathogen recognition to immune cell activation.

A significant advance occurred in the early 21st century with the characterization of Dectin-1, the first receptor identified to specifically recognize β-glucans in fungal cell walls (Ariizumi et al. 2000). Dectin-1 possesses a cytoplasmic ITAM that recruits and activates spleen tyrosine kinase (Syk) upon ligand binding; Syk activation triggers downstream signaling through the CARD9 pathway, leading to the activation of NF-κB and the production of pro-inflammatory cytokines and chemokines (Ariizumi et al. 2000, Adachi et al. 2004). This discovery marked a paradigm shift, revealing that CLRs are not merely involved in antigen capture but can also independently mediate sophisticated signal transduction events that drive immune activation.

Further research has uncovered considerable diversity and complexity within the CLR family. For example, Dectin-2 and Dectin-3 can form homo- or heterodimers to recognize α-mannans on fungal surfaces, transducing signals through association with the ITAM-containing Fc receptor γ chain (FcRγ) (L. L. Zhu et al. 2013). Meanwhile, Mincle not only identifies pathogen components such as trehalose-6,6'-dimycolate (TDM) but also senses endogenous ligands—like apoptotic cell-associated molecules—released upon tissue damage or stress, underscoring the role of CLRs in discriminating between self and non-self as well as detecting danger signals (Martinez-Lopez et al. 2019, Tanaka et al. 2020). This functional versatility underscores the importance of CLRs in maintaining immune surveillance.

In contrast to the immunostimulatory roles of the aforementioned receptors, CD206 (macrophage mannose receptor) exemplifies a CLR involved in immune regulation. Expressed predominantly on macrophages, particularly the anti-inflammatory M2-type, CD206 recognizes glycosylated ligands like mannose and fucose to mediate endocytosis and antigen presentation, contributing to tissue repair and homeostasis (Xu et al. 2020, van der Zande et al. 2021, Ray et al. 2025). This illustrates the dual nature of CLRs in modulating immune responses.

CLRs can not only specifically recognize cell wall components of fungi, bacteria, and other microorganisms (such as β-glucan and mannan) but also sense endogenous signal molecules released by host cell damage. This multi-level ligand recognition ability makes them a key hub connecting the intestinal microbiota, epithelial barrier integrity, and immune-inflammatory responses (Li et al. 2019). Therefore, in-depth study of the mechanisms of CLRs in IBD is of great significance for revealing the pathogenesis of IBD and finding new therapeutic targets.

The role of Dectin-1 in inflammatory bowel disease

Structure and signaling mechanisms of Dectin-1

Dectin-1, encoded by the CLEC7A gene, is a transmembrane receptor predominantly expressed on myeloid cells such as monocytes, macrophages, dendritic cells, and neutrophils (P. R. Taylor et al. 2002, Willment et al. 2005). Its structure includes an extracellular CRD, a transmembrane region, and an intracellular ITAM motif (Ariizumi et al. 2000). Different from some other CLRs, Dectin-1 has unique ligand recognition characteristics and can recognize polysaccharides and other ligands without relying on Ca²⁺ (Kalia et al. 2021). The receptor binds various ligands, with β-glucan being the principal one. It also interacts with other molecules including specific polysaccharides and proteins such as amyloid-β (Aβ), particularly the Aβ₄₂ isoform (Zhao et al. 2023). Dectin-1 mediates anti-fungal immune responses primarily through recognition of β-glucans in fungal cell walls (Kalia et al. 2021). Table 1 summarizes the key fungal species recognized by Dectin-1, along with their associated diseases and mechanisms of action.

Table 1.

Major pathogens, recognition mechanisms, and associated pathophysiological roles of Dectin-1.

Category	Representative species	Associated disease/model	Major signaling pathways	References
Fungi	Aspergillus fumigatus, Fusarium solani	Fungal keratitis, invasive pulmonary aspergillosis	CARD9-dependent pathway, MAPK signaling (activates NF-κB, leading to production of IL-1β, IL-6, TNF-α)	(Guibo et al. 2024, Werner et al. 2009, Xu and Xie 2018)
	Candida albicans	Inflammatory bowel disease (IBD), Ventilator-associated pneumonia (VAP)	Syk-dependent pathway, modulating intestinal inflammatory responses	(Guo et al. 2025, Iliev et al. 2012)
	Engyodontium	Idiopathic pulmonary fibrosis (IPF)	Raf1-dependent non-canonical pathway (induces pro-fibrotic factors like TGF-β and MMPs)	(Qiu et al. 2025)

Dectin-1 expression is directly regulated by the transcription factor PU.1 (C. Zhang et al. 2010). Studies indicate that leukotriene B4 (LTB4) enhances Dectin-1 transcriptional activity in macrophages via the GM-CSF/PU.1 axis without altering mRNA stability; during fungal infection, LTB4 production and Dectin-1 expression establish a positive feedback loop that amplifies immune responses, including phagocytosis, cytokine secretion, and neutrophil recruitment (Serezani et al. 2012).

Ligand binding induces phosphorylation of the tyrosine residue within Dectin-1’s intracellular ITAM-like sequence, leading to recruitment and activation of Syk. This process is proposed to involve receptor dimerization, which provides docking sites for the two SH2 domains of Syk despite Dectin-1 containing only a single ITAM-like sequence. Activated Syk signals through the CARD9-MALT1-Bcl10 complex to activate NF-κB and MAPK pathways, promoting the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β (LeibundGut-Landmann et al. 2007, Tsang et al. 2008, Drummond et al. 2011). Recent research highlights the stress-response protein valosin-containing protein (VCP)/p97 as a critical regulator in Dectin-1 signaling (Shao et al. 2024). Following receptor activation, VCP is recruited to the Syk complex and undergoes tyrosine phosphorylation; In conjunction with its cofactor UFD1, VCP facilitates the polyubiquitination and degradation of the negative regulator SHP-1, thereby relieving inhibition of Syk and potentiating inflammatory responses (Shao et al. 2024).

Dectin-1 can also activate NF-κB through a Raf-1-dependent non-canonical pathway. In specific contexts, such as recognition of the commensal fungus Engyodontium, this signaling induces the expression of pro-fibrotic factors like Arginase-1 and TGF-β, contributing to the pathogenesis of idiopathic pulmonary fibrosis (Qiu et al. 2025). Notably, Syk can drive CARD9-independent cytokine production via the MAPK cascade (Gringhuis et al. 2009). In Aspergillus fumigatus keratitis, Dectin-1 signaling through the MAPK pathway promotes macrophage polarization toward a pro-inflammatory M1 phenotype. This shift is characterized by increased CD86 expression and elevated levels of TNF-α, iNOS, IL-6, and IL-12, thereby exacerbating corneal inflammation (Gringhuis et al. 2009) (Fig. 1).

Figure 1.

Structural features and signaling pathways of key CLRs in immune responses. Dectin-1, recognizes β-glucans from fungi (e.g. Candida albicans, Aspergillus fumigatus) and certain bacteria. Upon ligand binding, Dectin-1 clusters and activates Syk kinase via its ITAM-like motif. Syk phosphorylates CARD9, leading to the recruitment of BCL10 and MALT1, forming the complex, which activates the canonical NF-κB pathway. Additionally, Dectin-1 can trigger the non-canonical NF-κB pathway through Raf-1-MAPK signaling, promoting pro-inflammatory cytokine production (e.g. TNF-α, IL-1β, IL-6). Mincle, recognizes glycolipids such as trehalose-6,6’-dimycolate (TDM, cord factor) from Mycobacterium tuberculosis and SAP130 from damaged cells. Ligand engagement induces Mincle dimerization and recruitment of the FcRγ adaptor, which contains ITAM motifs. FcRγ-associated Syk becomes activated, leading to CARD9-BCL10-MALT1 complex formation and canonical NF-κB activation, resulting in pro-inflammatory cytokine secretion and enhanced antimicrobial responses. Dectin-3 recognizes α-mannans from fungi (e.g. Malassezia, Candida tropicalis). Similar to Mincle, Dectin-3 pairs with FcRγ, and ligand binding activates Syk, initiating the CARD9-BCL10-MALT1 cascade and NF-κB-dependent inflammatory responses, including cytokine production. CD206 contains eight CTLDs and an FNII domain. It recognizes mannose-, fucose-, and N-acetylglucosamine-containing glycans on pathogens (e.g. fungi, mycobacteria) and apoptotic cells. Unlike Syk-coupled CLRs, MR primarily mediates endocytosis and antigen presentation rather than direct Syk/NF-κB activation.

Dectin-1 plays a critical role in diverse disease

Dectin-1 plays a key role in the physiological and pathological processes of various diseases such as cardiovascular diseases, neurological diseases, and tumors (Brown et al. 2002, Daley et al. 2017, Mata-Martinez et al. 2022, Wattenberg et al. 2023, S. Ye et al. 2023b). Multiple studies have shown that Dectin-1 has a significant impact on cardiac function. Inhibiting Dectin-1 can significantly improve cardiac function after ischemia-reperfusion and effectively reduce myocardial cell apoptosis (Fan et al. 2019). In addition, as a new non-classical receptor for angiotensin II (Ang II), Dectin-1 is closely related to cardiac remodeling and dysfunction and is expected to become a new target for the treatment of heart failure caused by hypertension (Ye et al. 2023a). In the field of neurology, Dectin-1 is involved in the neuroinflammatory process of Alzheimer’s disease and traumatic brain injury. Especially after ischemic stroke, the Dectin-1/Syk signaling pathway plays a crucial role (Ye et al. 2020). In chronic inflammatory diseases, the role of Dectin-1 cannot be ignored. It can induce caspase-11/4-mediated macrophage apoptosis, stimulate the secretion of chemokines, and exacerbate airway neutrophilic inflammation, worsening asthma symptoms (Cai et al. 2024).

The immunomodulatory role of Dectin-1 in inflammatory bowel disease

Dectin-1, a pattern recognition receptor specific for fungal β-glucans, plays a central role in antifungal immunity. Genetic deletion of Dectin-1 impairs the capacity of macrophages and neutrophils to recognize pathogens such as Candida albicans, resulting in defective TNF production even in the presence of opsonins (P. R. Taylor et al. 2007). In vivo, Dectin-1-deficient mice exhibit attenuated inflammatory cell recruitment, elevated fungal burden, and worsened invasive infection, highlighting the receptor’s non-redundant role in innate antifungal defense (Taylor et al. 2007).

Fungi, as integral components of the gut microbiota, contribute to IBD pathogenesis (Nash et al. 2017). Inflamed intestinal mucosa shows increased fungal abundance and diversity compared to non-inflamed tissue (Li et al. 2014, Li et al. 2018). Patients with UC display higher fungal loads, particularly of Candida albicans, alongside elevated mucosal Dectin-1 expression that correlates with disease activity (Azizollah et al. 2024). Human genetic studies further associate specific CLEC7A haplotypes (rs2078178-rs16910631, AG)with refractory UC, supporting a causal role for Dectin-1 in IBD (Iliev et al. 2012).

Fungal dysbiosis can upregulate glutaminolysis in CD4⁺ T cells via the Dectin-1–Syk–NF-κB signaling pathway, enhancing mitochondrial oxidative phosphorylation and promoting Th1/Th17 differentiation along with pro-inflammatory cytokine production (e.g. IFN-γ, IL-17A, TNF-α), thereby driving IBD progression (Yu et al. 2023). Notably, Dectin-1’s function may extend beyond fungal recognition. For instance, the protective effect observed in Dectin-1/Dectin-2 double-knockout mice against colitis was primarily mediated by alterations in the bacterial microbiome (e.g. increased abundance of Lachnospiraceae), rather than changes in fungal communities, which highlights the broad network functions of innate immune receptors in microbiota regulation (Wang et al. 2022).

The role of Dectin-1 in IBD exhibits marked context dependence and functional duality, exerting either pro-inflammatory or protective effects across different experimental models or disease stages. This complexity stems from Dectin-1’s broad regulatory capacity over microbial communities and its diverse signaling pathways. In the context of fungal infection, Dectin-1 mediates phagocytic clearance of commensal fungi and secretion of cytokines such as IL-17 and IFN-γ via the CARD9 signaling pathway, thereby maintaining mycobiota equilibrium (Iliev et al. 2012). Dectin-1 deficiency permits opportunistic fungi such as Candida tropicalis to overgrow and invade tissues, aberrantly activating Th1/Th17 immunity and exacerbating colitis (Iliev et al. 2012). Conversely, in the absence of pathogenic fungi, Dectin-1 activation induces intestinal epithelial cells to produce the antimicrobial peptide S100A8/A9 (calprotectin), which inhibits the growth of lactobacilli such as Lactobacillus murinus; Suppression of Dectin-1 signaling promotes lactobacillus proliferation, subsequently driving regulatory T-cell differentiation via dendritic cell- and macrophage-derived TGF-β and IL-10, thereby alleviating inflammation (Tang et al. 2015). Further research indicates that dietary β-glucans can be recognized by Dectin-1-expressing myeloid cells in the colonic lamina propria, inducing calprotectin expression via IL-17F to finely tune microbiota balance (Kamiya et al. 2018). Disruption of this pathway leads to Lactobacillus murinus expansion and enhanced resistance to colitis, suggesting that dietary components may directly modulate intestinal immunity through Dectin-1 and offering novel insights for dietary intervention in IBD (Kamiya et al. 2018).

Dectin-1 also regulates intestinal inflammation by modulating monocyte recruitment and synthesis of inflammatory mediators. Its absence reduces CCL2-dependent monocyte influx and suppresses leukotriene B4 production and caspase-1–mediated IL-1β secretion, collectively ameliorating colitis (Rahabi et al. 2020). Clinically, inflamed IBD intestines show upregulation of the Dectin-1/CCL2/LTA4H axis and downregulation of the mannose receptor, supporting the pathway’s disease relevance (Rahabi et al. 2020).

Notably, Dectin-1’s functions extend beyond fungal recognition and inflammation triggering. A key study revealed that Dectin-1 is a coreceptor for MUC2, the primary component of intestinal mucus, in inducing immune tolerance (Shan et al. 2013). In the small intestine, MUC2 uptake by dendritic cells leads to formation of a Dectin-1–galectin-3–FcγRIIB complex that activates a β-catenin–dependent tolerogenic pathway; nuclear β-catenin sequesters NF-κB p65, selectively inhibiting IL-12 while promoting anti-inflammatory factors such as IL-10 and TGF-β1 (Shan et al. 2013). This mechanism supports regulatory T-cell differentiation and oral tolerance, and its disruption exacerbates intestinal inflammation. In mice lacking MUC2 or Dectin-1, this tolerogenic axis is disrupted, manifesting as aggravated intestinal inflammation and impaired oral tolerance (Shan et al. 2013). Thus, in the context of IBD, dysregulation of Dectin-1 signaling may not only compromise immune defense but also disrupt intestinal immune tolerance, contributing to the initiation or exacerbation of chronic inflammation.

Regarding therapeutic strategies, precision interventions tailored to disease stage and individual microenvironmental characteristics are essential. For patients with inadequate fungal clearance or high need for epithelial barrier repair, Dectin-1 agonists such as lentinan (a β-glucan agonist) may be considered to enhance barrier protection. Lentinan activates Dectin-1, inducing IL-1β production in macrophages, which subsequently promotes group 3 innate lymphoid cells to secrete IL-22, thereby strengthening epithelial barrier function and antibacterial defense, and alleviating colitis (Zhang et al. 2025). In cases where excessive Dectin-1 activation exacerbates inflammation, antagonists (e.g. laminarin) or downstream signaling inhibitors could be employed to mitigate inflammatory responses (Tang et al. 2015). Future clinical trials should focus on personalized treatment within a precision medicine framework, integrating multi-omics data and microenvironmental features to balance the dual roles of Dectin-1 in host defense and inflammatory regulation, ultimately advancing breakthroughs in IBD therapy.

The role of Mincle in inflammatory bowel disease

Structure, signaling, and functional roles of Mincle in inflammation and diseases

Mincle (macrophage-inducible C-type lectin), encoded by the CLEC4E gene, is primarily expressed on the surface of antigen-presenting cells such as macrophages, monocytes, and dendritic cells (Lu et al. 2018, Huang et al. 2023). Its structure includes an extracellular CRD, a transmembrane region, and an intracellular ITAM motif. Initially identified as a receptor for mycobacterial cell wall glycolipids—including trehalose-6,6'-dimycolate (TDM, or cord factor)—Mincle was also found to recognize endogenous alarmins released by necrotic cells, such as the histone deacetylase complex subunit SAP130 (Yamasaki et al. 2008, Ishikawa et al. 2009, Matsunaga and Moody 2009, Lee et al. 2012, Patin et al. 2017). Subsequent research has expanded its ligand repertoire to include microbial components like phenolic glycolipid-III (PGL-III) (Ishizuka et al. 2023) and endogenous DAMPs, such as β-glucosylceramide (β-GluCer) (Nagata et al. 2017, Zhang et al. 2022a, Zhang et al. 2023) and peroxiredoxin-1 (Prdx1) (Li et al. 2023). Upon ligand engagement, Mincle recruits the Syk through the adapter FcRγ chain, leading to activation of the NF-κB and MAPK signaling pathways. This cascade promotes the secretion of pro-inflammatory cytokines and chemokines, including IL-6, IL-1β, TNF-α, MIP-2, and KC (Fig. 1) (Yamasaki et al. 2008). In infectious diseases, Mincle detects pathogen-associated glycolipid components, such as TDM from mycobacteria and α-mannans from Candida species, thereby activating immune cells and initiating defensive inflammatory responses. In autoimmune contexts, however, Mincle contributes to inflammation by sensing DAMPs, such as the endogenous nuclear protein SAP130 released by injured or dying cells, which promotes sustained inflammatory signaling and exacerbates disease progression (Huang et al. 2023, Zou et al. 2024). A summary of its ligands and functional roles is provided in Table 2.

Table 2.

Major pathogens, recognition mechanisms, and associated pathophysiological roles of Mincle.

Category	Specific pathogen	Recognition mechanism	Role in disease	Associated diseases	References
Fungi	Malassezia spp.	α-mannosyl residues	Initiates macrophage production of inflammatory cytokines (e.g. MIP-2, TNF-α, IL-10, KC) to combat skin infections	Pityriasis versicolor, atopic dermatitis, fatal sepsis	(Yamasaki et al. 2009)
	Candida albicans (specific strains)	Recognizes strain-specific structures	Promotes TNF-α production; Mincle-deficient mice show increased susceptibility to systemic candidiasis	Systemic candidiasis	(Wells et al. 2008)
Bacteria	Staphylococcus aureus	The bacterial glycolipid Glc-DAG	Limited role under normal expression; ectopic overexpression causes severe lung pathology, bacterial proliferation, and lethal pneumonia	Staphylococcal pneumonia	(Hollwedel et al. 2024)
	Mycobacterium tuberculosis	Trehalose-6,6'-dimycolate (TDM)	Induces inflammatory cytokines/chemokines and granuloma formation to restrict bacterial spread; acts as a vaccine adjuvant; disrupts phagosome maturation; induces IL-10; evades recognition by producing glucose monomycolate	Tuberculosis	(Lang 2013, Olvany et al. 2020, Rungelrath et al. 2024)
	Mycobacterium leprae	Phenolic glycolipid-III (PGL-III)	PGL-III analogs show a unique recognition pattern, binding multiple Mincle molecules	Leprosy	(Ishizuka et al. 2023)

The immunomodulatory role of Mincle in inflammatory bowel disease

Mincle plays a significant role in the pathogenesis of IBD by recognizing both PAMPs and DAMPs, thereby modulating the gut microbiota and disease progression. Under homeostatic conditions, Mincle contributes to the regulation of microbiota-driven Th17 cell differentiation. Dendritic cells in Peyer’s patches engage the Mincle–SYK signaling axis to detect commensal bacteria, resulting in the production of cytokines such as IL-6 and IL-23p19. These cytokines in turn modulate T cells and innate lymphoid cells (ILCs), fine-tuning the secretion of IL-17 and IL-22, which supports epithelial barrier integrity and limits microbial translocation (Martinez-Lopez et al. 2019). This regulatory cascade not only enhances intestinal barrier function but also effectively restricts microbial translocation.

During mucosal damage, elevated levels of endogenous DAMPs—including S100A8/S100A9, HMGB1, galectins, and SAP130—are observed (Gong et al. 2020a, Boyapati et al. 2016). Notably, serum levels of SAP130 are significantly increased in patients with active Crohn’s disease and correlate with disease severity (Gong et al. 2020a). Upon release, SAP130 activates Mincle in macrophages via the FcRγ chain, triggering SYK-dependent signaling that enhances the production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, thereby amplifying intestinal inflammation in IBD (Gong et al. 2020b, Yamasaki et al. 2008, Li et al. 2024).

Furthermore, Mincle plays an essential role in the induction of trained immunity (TI) in bone marrow progenitors (BMPs). During the development of colitis, increased intestinal permeability permits gut bacteria such as Enterococcus faecalis to translocate to the bone marrow in mice, where they trigger TI in BMPs. There, they induce a persistent state of innate immune reprogramming in BMPs, characterized by enhanced inflammatory responses upon secondary stimulation. This TI phenotype exerts a dual role: it can confer protection against subsequent infections while also potentiating pathological inflammation in sterile contexts (Robles-Vera et al. 2025). Studies in Clec4e–deficient mice have demonstrated impaired TI following Enterococcus faecalis challenge, along with significantly attenuated pathological changes after dextran sulfate sodium (DSS) administration compared to wild–type mice. These findings provide critical insights into the interplay between gut microbial translocation and the immune system, and highlight Mincle as a promising target for novel vaccine strategies based on TI modulation (Robles-Vera et al. 2025). These observations position Mincle at the intersection of microbial translocation and innate immune memory, suggesting its utility as a target for vaccines or immunomodulators aimed at inducing or dampening TI.

Current therapeutic strategies targeting Mincle focus on the development of inhibitors and small-molecule antagonists that block its signaling pathway to alleviate inflammation. Several candidate agents have shown efficacy in animal models. For example, a highly specific neutralizing DNA aptamer (AptMincle) has been reported to bind both human and murine Mincle, suppressing its activation (Stephens et al. 2022). In vitro, AptMincle effectively blocks Syk and NF-κB phosphorylation induced by Mincle agonists like TDM. Moreover, in a DSS-induced colitis model, biologically stabilized AptMincleDRBL reduced disease activity in a dose-dependent manner (Stephens et al. 2022). These results underscore the potential of targeting Mincle as a novel therapeutic strategy for inflammatory bowel disease (IBD). Nevertheless, the clinical translation of Mincle–targeted agents faces several challenges, including insufficient drug specificity and safety concerns. Future studies should aim to further elucidate the molecular mechanisms governing Mincle activation and signaling, identify more precise and potent inhibitors, and clarify Mincle’s functional interactions with other immune molecules under different disease contexts. Such efforts will be essential for developing personalized treatment regimens targeting Mincle in inflammatory disorders.

The role of Dectin-3 in inflammatory bowel disease

Structure, signaling, and functional roles of Dectin-3

Dectin-3 (CLEC4D) is a transmembrane protein receptor mainly expressed on the surface of immune cells such as monocytes, dendritic cells, and macrophages (Arce et al. 2004, Graham et al. 2012). Its structure includes an extracellular CRD, a transmembrane region, and a cytoplasmic domain, but unlike Dectin-1 and others, Dectin-3 is not directly associated with classical signal adaptor molecules such as FcRγ chain or DAP12. Its intracellular signal transduction mechanism is relatively unique, potentially involving heterodimer formation with other receptors or interactions with unidentified adaptor molecules to activate downstream pathways such as the Syk–NF–κB axis, leading to the production of inflammatory cytokines including TNF–α and IL–1β (Graham et al. 2012).

Dectin-3 recognizes a range of fungal cell wall components, particularly α-mannans present on Candida albicans hyphae (Balch et al. 1998, Zhu et al. 2013, Zhu et al. 2021). This receptor plays significant roles in several inflammatory and infectious contexts. During fungal infections, Dectin-3 contributes to host defense by sensing invasive fungi, activating immune cells, and promoting antifungal responses. In autoimmune settings, it may also participate in disease pathogenesis by modulating immune cell functions and inflammatory intensity (Li et al. 2021). Furthermore, Dectin-3 plays a critical role in tumorigenesis and progression. For instance, in hepatocellular carcinoma (HCC), macrophages—key immune cells driving tumor progression within the tumor microenvironment (TME)—exhibit functional states closely associated with their metabolic activity (Van den Bossche et al. 2017, Wen et al. 2021, Cheng et al. 2022, Qu et al. 2022). Dectin3 modulates the TME by suppressing glycolytic metabolism in macrophages, leading to increased T cell infiltration and reduced presence of tumor-associated macrophages. This metabolic reprogramming ultimately inhibits the proliferation of H22 cells and promotes their apoptosis (Qu et al. 2022). The major fungal species recognized by Dectin-3, their recognition mechanisms, and the associated diseases and functional mechanisms are summarized in Table 3.

Table 3.

Fungal recognition profile and pathophysiological roles of Dectin-3.

Category	Specific pathogen	Mechanism	Role in disease	Associated diseases	References
Fungi	Candida albicans	Recognizes α-mannan on the fungal cell wall	Dectin-3 deficiency impairs fungal clearance, exacerbating intestinal inflammation and increasing colorectal cancer risk	IBD, colorectal cancer	(Zhu et al. 2013, Zhu et al. 2021)
	Candida tropicalis	Recognizes α-mannan	Dectin-3 deficiency leads to increased fungal load and aggravated intestinal inflammation	Colitis	(Wang et al. 2016)
	Paracoccidioides brasiliensis	α-mannans on its cell wall are recognized by the Dectin-2/Dectin-3 heterodimer	Activates the Syk signaling pathway, triggers NLRP3 inflammasome activation, and promotes the secretion of IL-1β and Type I interferons	Fungal infectious disease, Paracoccidioidomycosis	(Preite et al. 2018)

The immunomodulatory role of Dectin-3 in inflammatory bowel disease

Dectin-3 modulates intestinal fungal abundance, such as that of Candida albicans, thereby influencing macrophage immune responses and fungal clearance capacity. Dysregulation of Dectin-3 disrupts the repair process of the intestinal epithelial barrier, contributing significantly to the pathogenesis of IBD. In DSS-induced colitis models, Dectin-3-deficient (Clec4d⁻/⁻) mice exhibit more severe disease phenotypes, primarily attributable to the specific expansion of the commensal fungus Candida tropicalis and a consequent defect in innate immune responses (Wang et al. 2016). Mechanistically, the absence of Dectin-3 impairs the phagocytic and fungicidal capacity of macrophages against C. tropicalis (Wang et al. 2016). It disrupts the formation of the CARD9/Bcl10 complex, leading to suppressed NF-κB signaling pathway activation and reduced production of key cytokines such as IL-6 and TNF-α (Wang et al. 2016). This impairment not only weakens antifungal immunity but also compromises the ability of macrophage-derived factors to promote STAT3 phosphorylation and migration for repair in colonic epithelial cells. Notably, antifungal therapy (e.g. fluconazole) significantly alleviates colitis severity in Clec4d⁻/⁻ mice (Wang et al. 2016).

At the molecular level, Dectin-3 forms a heterodimeric pattern-recognition receptor with Dectin-2. This heterodimer exhibits a higher binding affinity for α-mannans than their respective homodimers, substantially enhancing the sensitivity for detecting fungal infections and playing a critical role in host defense against Candida albicans (Zhu et al. 2013). Downstream, the Dectin-3/Dectin-2 heterodimer recruits Syk via the FcRγ chain, activating the CARD9/Bcl10/MALT1 signaling axis. This cascade drives NF-κB activation, induces the production of pro-inflammatory cytokines like TNF-α and IL-6, and promotes Th17 cell differentiation, illustrating a mechanism by which CLRs achieve recognition diversity through heterodimerization (Zhu et al. 2013). Furthermore, Dectin-2/3-Syk signaling is essential for activating the E3 ubiquitin ligase c-Cbl in dendritic cells upon α-mannan stimulation (Duan et al. 2021). The c-Cbl/RelB axis plays a vital role in regulating fungus-induced intestinal inflammation and maintaining homeostasis. Specifically, c-Cbl mediates the ubiquitination and degradation of the non-canonical NF-κB subunit RelB. In c-Cbl-deficient DCs, α-mannan-induced RelB activation is enhanced, while p65-mediated transcription of the anti-inflammatory cytokine gene IL-10 is suppressed, ultimately exacerbating DSS-induced colitis (Duan et al. 2021).

In the context of colorectal cancer, Dectin-3 suppresses tumor development by regulating the gut mycobiota (Bergmann et al. 2017, Bhatt et al. 2018, Zhu et al. 2021). Dectin-3 deficiency impairs macrophage clearance of Candida albicans, resulting in an increased fungal burden. The increase in Candida albicans leads to an increase in IL-7/IL-22 through the HIF-1-dependent glycolysis regulation, ultimately resulting in an elevated p-STAT3 level in epithelial cells and tumor progression (77). Additional studies indicate that the gut fungus C. tropicalis can enhance the immunosuppressive function of myeloid-derived suppressor cells through the Dectin-3-Syk-PKM2-HIF-1α-glycolysis signaling axis, thereby promoting colorectal cancer progression (Zhang et al. 2022c).

The role of the mannose receptor in inflammatory bowel disease

Structure and functional roles of mannose receptor

The mannose receptor (MR), also known as CD206, is a single-pass transmembrane protein composed of a fibronectin type II (FNII) domain, eight CTLDs, a transmembrane domain, and a short C-terminal cytoplasmic tail (East and Isacke 2002) (Fig. 1). CD206 is expressed in macrophages, dendritic cells, endothelial cells(East and Isacke 2002, Martinez-Pomares 2012, van der Zande et al. 2021), and has functions such as clearing endogenous molecules, promoting antigen presentation, and regulating cell activation and transport (Martinez-Pomares 2012). This receptor binds and internalizes a diverse array of endogenous ligands. These include chondroitin sulfates A and B, sulfated Lewis a/x oligosaccharides, and sulfated N-glycans such as those found on lutropin. These interactions are implicated in modulating the migration and function of CD206-positive cells, playing roles in immune responses, hormone clearance, and intercellular communication (Leteux et al. 2000). CD206 also recognizes pathogens by efficiently binding carbohydrate structures commonly found on their surfaces, such as mannose, fucose, and N-acetylglucosamine (Stahl et al. 1978, Shepherd et al. 1981, Taylor et al. 1992). Different regions of CD206 are responsible for binding to different ligands. For example, the cysteine-rich region mediates the binding to sulfated sugars, its FNII structural domain binds to collagen and mediates the internalization of collagen by macrophages and hepatic sinusoidal endothelial cells, and its CTLDs are responsible for recognizing glycoconjugates.(Martinez-Pomares 2012, van der Zande et al. 2021). In summary, CD206 can recognize a variety of endogenous and exogenous ligands, maintain systemic homeostasis, and mediate immune responses. The major pathogens recognized by CD206, their recognition mechanisms, and the associated diseases and functional mechanisms are summarized in Table 4.

Table 4.

Major pathogens, recognition mechanisms, and associated pathophysiological roles of CD206.

Category	Specific pathogen	Recognition ligand	Role in disease mechanism	Associated diseases	References
Fungi	Mycobacterium tuberculosis	Mannosylated ligands on the pathogen surface (e.g. mannan-coated cell wall)	The pathogen utilizes endocytosis as a ‘Trojan horse’ to enter macrophages, achieving internalization and establishing an infectious focus	Tuberculosis.	(Azad et al. 2014, Diaz-Silvestre et al. 2005, Thalla et al. 2020)
Bacteria	Streptococcus pneumoniae (Pneumolysin, PLY)	Cholesterol-binding loop	Peptides derived from MRC-1 can effectively neutralize the virulence effects of various bacterial toxins	Infectious diseases	(Subramanian et al. 2020)
Virus	HIV	Enriched mannose glycans	The interaction between CD206 and the HIV envelope protein promotes viral entry into macrophages during early infection, but becomes restrictive after the infection is established; the virus, in turn, employs proteins such as Vpr and Nef to evade this restriction, thereby facilitating robust viral replication and subsequent transmission.	AIDS	(caused by HIV infection) (Lubow et al. 2020)

The immunomodulatory role of mannose receptor in inflammatory bowel disease

CD206 plays multifaceted roles in the pathogenesis of IBD, functioning as a critical modulator of intestinal immune homeostasis. On one hand, CD206 participates in antigen presentation by recognizing mannosylated molecules within the intestinal environment, regulating immune cell functions and influencing T-cell activation and differentiation. For instance, CD206 enhances the maturation and antigen-presenting capacity of dendritic cells (Liu et al. 2021). On the other hand, CD206 modulates macrophage polarization and phagocytic activity, impacting inflammatory responses and intestinal barrier integrity (Wright et al. 2021). The dynamic expression of CD206 during macrophage differentiation has been identified as a key regulator of intestinal immune balance. During monocyte-to-macrophage differentiation, CD206 expression significantly increases alongside the upregulation of anti-inflammatory genes and downregulation of pro-inflammatory genes (Rivollier et al. 2012, Bain et al. 2013, Wright et al. 2021). It is worth noting that CD206 can be used as a specific marker to distinguish the maturity of macrophages: CD206⁺ cells highly express mature markers such as CD163, CD68, and CD209 and show stronger efferocytosis and anti-inflammatory activity, while CD206⁻ cells exhibit an immature phenotype with more prominent pro-inflammatory characteristics (Rivollier et al. 2012, Bain et al. 2013, Wright et al. 2021). Mouna Rahabi et al.’s team confirmed through gene knockout experiments that the deletion of CD206 disrupts the differentiation homeostasis of macrophages, leading to the exacerbation of DSS-induced mouse colitis (Rahabi et al. 2020).

Although multiple studies have suggested an increase in the proportion of immature macrophages in the intestine of IBD patients, Wright et al. found through single-cell sequencing that the ratio of CD206⁺ to CD206⁻ cells in the colonic mucosa of IBD patients during the active phase has no significant difference from that of healthy controls (Bernardo et al. 2018, Chapuy et al. 2019, Wright et al. 2021). This divergence may be due to: CD206⁻ cells still retain differentiation potential in the inflammatory microenvironment and can transform into a mature phenotype after being recruited to the lesion site; the impact of IBD subtypes (CD vs. UC) on the dynamic expression of macrophage differentiation pathways. Therefore, intervention strategies targeting newly recruited monocytes may achieve therapeutic effects by regulating their terminal differentiation direction.

Current research based on the biological properties of CD206 has led to the development of two innovative therapeutic approaches. First, the bioactive fish-derived peptide Naticol®Gut, which targets CD206, polarizes macrophages toward an anti-inflammatory and antioxidant phenotype while attenuating inflammatory responses in CD4⁺ and CD8⁺ T cells in a macrophage-dependent manner, thereby alleviating DSS-induced colitis in mice (Rahabi et al. 2022). Notably, Naticol^®Gut-treated IBD patients also exhibited pronounced anti-inflammatory and antioxidant phenotypes in their peripheral blood monocytes (Rahabi et al. 2022). Second, polymeric nanoparticles functionalized with mannose—such as PLGA-PEG-mannose nanoparticles—demonstrate enhanced accumulation of model antigens (e.g. ovalbumin) in inflamed colonic tissues, indicating that active targeting of immune cells via mannose-mediated delivery improves therapeutic efficacy in IBD (Coco et al. 2013). These findings underscore CD206 as a promising target for site-specific drug delivery in inflamed intestinal tissues.

Despite the therapeutic potential of CD206-targeted strategies, several challenges remain: balancing the anti-inflammatory effects mediated by CD206 against potential risks of immune suppression; addressing the heterogeneity of CD206 expression dynamics across IBD subtypes and disease stages; and developing delivery systems capable of penetrating the intestinal mucosal barrier.

Conclusion

CLRs play a complex and important role in the occurrence and development of IBD. CLRs such as Dectin-1, Mincle, Dectin-3, and CD206 recognize PAMPs and DAMPs in the intestine, activate downstream signaling pathways, and regulate the function of immune cells and the intensity of inflammatory responses. The structural features, major ligands, relevance to IBD, and pharmacological modulators of these CLRs are summarized in Table 5. These receptors may play different roles in different cell types and tissue microenvironments and have complex interactions with each other. For example, Dectin-1 and Mincle can promote the secretion of inflammatory cytokines by activating the Syk-NF-κB signaling pathway after recognizing fungal ligands; while CD206 regulates the inflammatory response and barrier function of the intestine by regulating the polarization and phagocytic function of macrophages. In addition, CLRs are closely related to the intestinal microbiota. The composition and metabolic products of the intestinal microbiota may affect the expression and function of CLRs, while CLRs can also regulate the diversity and stability of the intestinal microbiota.

Table 5.

Key features of CLRs in inflammatory bowel disease.

Feature	Dectin-1 (CLEC7A)	Mincle (CLEC4E)	Dectin-3 (CLEC4D)	CD206 (macrophage mannose receptor)
Structure	Type II transmembrane protein with a single extracellular CRD and a cytoplasmic ITAM motif(Ariizumi et al. 2000)	Type II transmembrane protein with a single extracellular CTLD. Associates with the FcRγ chain for signaling via its ITAM(Huang et al. 2023)	Type II transmembrane protein with a single extracellular CTLD. Often forms heterodimers with Dectin-2 to broaden ligand recognition (Graham et al. 2012, Zhu et al. 2013)	Type I transmembrane protein with multiple extracellular CTLDs and a fibronectin type II domain. Does not signal via ITAM (East and Isacke 2002)
Major ligands	β-1,3/β-1,6-glucans from fungal cell walls) (Iliev et al. 2012)	Exogenous: TDM. Endogenous: SAP130 (Huang et al. 2023)	α-mannans from fungal cell walls (Wang et al. 2016)	Mannose, fucose, N-acetylglucosamine residues on microorganisms and host glycoproteins (Azad et al. 2014)
Relevance to IBD	Dual role: - Pro-inflammatory: Recognizes fungi, exacerbating Th1/Th17 inflammation. - Protective: Promotes epithelial repair via IL-22; induces regulatory T-cells with certain ligands. Function is highly context-dependent (Iliev et al. 2012, Tang et al. 2015, Yu et al. 2023, Zhang et al. 2025)	Potential role in amplifying inflammation through recognition of commensal or pathobiont bacteria and endogenous DAMPs released during intestinal damage (Gong et al. 2020a, Martinez-Lopez et al. 2019)	May influence IBD progression by enhancing immune responses to gut fungi. Likely pro-inflammatory during fungal dysbiosis(Wang et al. 2016, Zhu et al. 2013)	Protective role: - Expressed on regulatory macrophages; helps maintain intestinal homeostasis. - Loss of function or expression may contribute to IBD pathogenesis(Rahabi et al. 2020, Wright et al. 2021)
Pharmacological modulators	Agonists: Laminarin (antagonist context-dependent), soluble β-glucans.(Zhang et al. 2025)	Antagonists: small-molecule inhibitors (Stephens et al. 2022)	Currently, no specific clinical-stage modulators are available; research relies mainly on genetic tools (e.g. antibodies)	Targeting strategy: mannosylated nanoparticles are used to deliver anti-inflammatory drugs specifically to macrophages in inflamed intestines (Coco et al. 2013, Rahabi et al. 2022)

Although substantial evidence supports the importance of CLRs in IBD pathology, conflicting results and context-dependent phenomena highlight the complexity of their functions. For example, the loss-of-function polymorphism c.714T > G (p.Y238X) in Dectin-1 would theoretically attenuate inflammatory responses by impairing fungal recognition, potentially conferring protection against IBD (de Vries et al. 2009). However, large-scale genetic association studies have shown no significant difference in allele frequency between patients and healthy controls, nor any clear correlation with clinical features (de Vries et al. 2009). This discrepancy may stem from the polygenic nature of IBD, signaling redundancy—where other CLRs (e.g. Dectin-2, Mincle, or CD206) compensate for impaired Dectin-1 function—and variations in genetic background, environmental exposures, and microbial composition across populations.

In the context of personalized medicine, CLRs gene polymorphisms may influence individual susceptibility to IBD and response to treatment. Although the Dectin-1 c.714T > G polymorphism is not a major genetic risk factor for IBD, it may interact with other variants to shape disease phenotypes or therapeutic outcomes (de Vries et al. 2009). Moreover, the expression patterns of CLRs and associated molecules offer potential as biomarkers for disease subtyping and activity assessment. Studies have shown that active UC patients exhibit significantly elevated expression levels of Dectin-1 in the intestinal mucosa compared to those with non-active disease and healthy controls(Azizollah et al. 2024). Similarly, increased expression of Dectin-3 and CARD9 in IBD patients is closely associated with disease severity (DU 2019) These findings suggest that CLRs expression profiles could serve as useful tools for IBD diagnosis and stratification. Another promising direction is the use of CLRs expression patterns to classify IBD subtypes. The high heterogeneity of IBD is a major cause of treatment failure. Integrating CLRs expression profiles, microbial composition, and clinical features may help identify patient subgroups that are more responsive to specific targeted therapies. For example, patients with high Dectin-1 expression and fungal dysbiosis might benefit more from anti-Dectin-1 therapy, while those with low CD206 expression could respond better to CD206 agonists.

Future research on CLRs in IBD should advance along several interconnected fronts to bridge current knowledge gaps and facilitate clinical translation. Key priorities include elucidating cell-type and tissue-microenvironment-specific functions of CLRs using single-cell sequencing technologies, which can map expression patterns and interaction networks across immune cell subsets and intestinal niches. Complementary proteomic and bioinformatic approaches are needed to systematically identify CLR-interacting partners and signaling complexes, potentially revealing opportunities for multi-receptor targeting. For example, co-regulating Dectin-1 and the mannose receptor may achieve synergistic anti-inflammatory effects while minimizing immunosuppressive risks compared with single-receptor modulation (Rahabi et al. 2020). Another promising avenue involves investigating microbiome-mediated CLR regulation, particularly how gut microbiota and their metabolites indirectly shape receptor activity. Beneficial microbial metabolites, such as short-chain fatty acids (SCFAs), may exert anti-inflammatory effects by directly or indirectly regulating CLR signaling pathways. Butyrate, for example, suppresses inflammatory activity in macrophages and neutrophils by reducing the production of cytokines such as TNF-α and IL-1β, inhibiting neutrophil migration, and attenuating the formation of neutrophil extracellular traps (NETs), thereby alleviating mucosal inflammation (Mukhopadhya and Louis 2025), These effects are mediated in part through histone deacetylase (HDAC) inhibition and signaling via G protein-coupled receptors such as GPR109A, pathways that may crosstalk with and regulate inflammatory cascades triggered by CLR activation. Furthermore, studies suggest that specific lipid derivatives generated by Helicobacter pylori from host cholesterol can activate CLRs like Mincle and Dendritic cell immunoactivating receptor, implying that analogous mechanisms may operate in fungal-CLR interactions (Nagata et al. 2021). Finally, Translational validation of CLRs-targeted agents, including small-molecule inhibitors, monoclonal antibodies, and gene therapies, in disease-relevant models and clinical cohorts remains critical for assessing efficacy and safety. For instance, Dendritic cell immunoreceptor blockade has been shown to mitigate colitis and suppress colorectal tumor growth by enhancing the GM-CSF–STAT5 pathway, highlighting the therapeutic potential of targeting specific CLRs (Sun et al. 2022).

In conclusion, CLRs have important significance in the research of IBD. Although some progress has been made at present, further in-depth study of their mechanisms, interrelationships, and clinical application potential is still needed to provide new ideas and methods for the diagnosis and treatment of IBD.

Funding

This work was supported by the National Natural Science Foundation of China (82271803); National Natural Science Foundation of ShanDong Province (ZR2024QH157); Joint Innovation Team for Clinical & Basic Research (202409), Shandong First Medical University.

Conflicts of interest

No potential conflict of interest was reported by the author(s).