Transforming growth factor β-activated kinase 1 as a central integrator of immune-microbiota crosstalk in colitis (Review)

Abstract

Colitis, particularly ulcerative colitis, involves the convergence of epithelial barrier disruption, innate immune activation and microbiota dysbiosis. Transforming growth factor β-activated kinase 1 (TAK1; also known as MAP3K7) is positioned at this interface because it integrates signals downstream of tumor necrosis factor (TNF) receptors, Toll-like receptors and interleukin (IL)-1 receptors, and activates nuclear factor-κB and mitogen-activated protein kinase pathways, which control cytokine production, epithelial survival and tissue repair. Current evidence supports a cell type- and disease stage-specific model for TAK1 rather than a uniform pro-inflammatory role. In intestinal epithelial cells, TAK1 preserves barrier integrity by limiting TNF receptor 1 (TNFR1)-proximal death signaling mediated by TNFR1-associated death domain protein and receptor-interacting serine/threonine-protein kinase 1, and by supporting repair. In myeloid cells, TAK1 can amplify inflammatory pathways through modulation of the signaling gain of the TAK1/TAK1-binding protein signalosome, ubiquitin modification and scaffold-dependent pathway coupling. Evidence from dendritic cells and adaptive immune circuits further indicates that TAK1 outputs can restrain IL-23 production, promote IL-27/type 1 regulatory T cell-associated barrier protection and maintain immune regulatory capacity. These divergent functions create a therapeutic paradox: Global TAK1 inhibition may suppress inflammatory amplification but may also compromise epithelial survival and barrier maintenance. Future studies should prioritize cell-type-specific TAK1 activity profiling, identifying biomarkers that distinguish inflammatory amplification from repair-competent states, and investigating output-based or compartment-targeted strategies that modulate pathogenic TAK1 signaling while preserving epithelial protection.

1. Introduction

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease, is characterized by chronic, relapsing inflammation of the gastrointestinal tract (1). Colitis pathogenesis involves a complex interplay between genetic susceptibility, dysregulated immune responses, epithelial barrier dysfunction and perturbations of the gut microbiota (2). Signaling pathways that control cytokine production, epithelial cell death and immune cell activation are central to the inflammatory cascade in colitis (3). In particular, activation of the transcription factor nuclear factor-κB (NF-κB) and various mitogen-activated protein kinases (MAPKs), including c-Jun N-terminal kinase (JNK) and p38, in intestinal epithelial and mucosal immune cells leads to the induction of numerous inflammatory mediators [such as tumor necrosis factor (TNF), interleukins (ILs) and chemokines] that drive and perpetuate mucosal inflammation (4). These pathways are tightly regulated under normal conditions to maintain mucosal homeostasis; however, in IBD, they become aberrantly activated, resulting in excessive inflammation and tissue injury (1,2,5).

Transforming growth factor β-activated kinase 1 (TAK1; also known as MAP3K7) is a central signaling hub in the inflammatory and epithelial stress responses. Recent colitis-related studies have associated TAK1 pathways with specific disease contexts, including macrophage pyroptosis associated with anti-TNF non-response and epithelial death pathway control involving TNF receptor 1 (TNFR1)-associated death domain protein (TRADD) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) modules. However, these findings support a context-specific role for TAK1 rather than a generalized claim of uniform TAK1 activation across all forms of IBD (6,7). Originally identified in the context of TGF-β and bone morphogenetic protein signaling (8), TAK1 is now well established as an essential kinase that mediates signals from pro-inflammatory cytokines, including TNF and IL-1β, and innate immune receptors, including Toll-like receptors (TLRs), to downstream NF-κB and MAPK molecules (9-11). Through these pathways, TAK1 induces genes encoding the cytokines IL-1β and IL-6 and the transcription factors interferon regulatory factor 1, NKX3.1 and JUN, and supports NF-κB-dependent anti-apoptotic programs; in the intestine, its contribution to tissue repair is reflected primarily by the preservation of epithelial survival and barrier continuity (7,9,12-14). TAK1 serves a context-dependent role: In some settings, it promotes inflammation by activating NF-κB and MAPK signaling, whereas in others it is required for cell survival and homeostatic barrier function (13-15). This duality is exemplified by intestinal epithelial TAK1 deletion, which disrupts cytoprotective signaling, increases epithelial apoptosis and barrier loss and aggravates experimental ileitis or colitis, whereas pharmacological TAK1 inhibition can reduce inflammatory cytokine production and disease severity in models dominated by inflammatory non-epithelial cells (14-16).

In UC, the major inflammatory inputs that converge on TAK1 are consistent with established disease mechanisms. TNF and IL-1β are abundant in the inflamed mucosa, whereas epithelial barrier damage and dysbiosis increase exposure to TLR ligands and other microbial products. These signals engage TNFR, IL-1 receptor (IL-1R) and TLR pathways, which converge on TAK1-containing complexes upstream of NF-κB and MAPKs. Therefore, UC provides a setting in which TAK1 can connect epithelial stress, microbial sensing and mucosal cytokine amplification. However, the net effect of TAK1 pathways depends on whether signaling occurs in epithelial, myeloid, dendritic or adaptive immune compartments (1,3,4,9-16). Previous TAK1-focused reviews have examined vascular signaling and cell type-specific innate immune functions (9,13). By contrast, the present review places TAK1 within a UC-specific immune-microbiota feed-forward circuit and compares epithelial protection with inflammatory and regulatory outputs across cell compartments and disease stages. This framework highlights the epithelial safety paradox of global TAK1 inhibition and supports compartment- and output-selective therapeutic strategies.

2. Immune-microbiota dysregulation in UC: Signaling context for TAK1

Macrophage polarization in UC

Macrophages in the intestinal lamina propria exhibit remarkable plasticity, differentiating into either pro-inflammatory M1 or anti-inflammatory M2 phenotypes (17). M1 macrophages, typically induced by interferon-γ (IFN-γ) or microbial lipopolysaccharide (LPS), produce TNF-α, IL-1β, IL-6, IL-12, nitric oxide and reactive oxygen species, thereby promoting epithelial injury and leukocyte recruitment (17-20). M2-like macrophages, shaped by IL-4, IL-13, IL-10 or tissue repair cues, contribute to the resolution of inflammation, matrix remodeling and mucosal healing (21-23). In UC, this balance shifts toward pro-inflammatory macrophage states, particularly during active and chronic disease (24,25). In this macrophage-centered framework, TAK1 is primarily relevant as an upstream signal integrator for TNF, IL-1R, TLR and NF-κB/MAPK pathways, rather than as a separate macrophage phenotype marker.

Mechanistically, a proposed model suggests that C-C motif chemokine ligand 3 and C-C motif chemokine receptor 1 may promote M1 polarization, leading to inducible nitric oxide synthase activation and oxidative stress, thereby triggering NF-κB-driven cytokine production and mucosal injury (22). Conversely, M2 macrophage polarization is frequently characterized by canonical markers, including ARG1, CD206/MRC1 and IL-10, and is associated with anti-inflammatory and tissue repair functions (23). In mouse and human intestinal samples, macrophages are experimentally verified by flow cytometry based on F4/80 expression, while M2-like macrophages are further identified based on CD206 expression (24). At single-cell resolution, macrophages can be further subdivided into refined states, including reference definitions of M1 (CD86^low CD163^high GBP1^high), M2b (CD163^low HLA-DRB5^low STAT3^high) and M2d (CD86^low CD163^high IL10^high) (22). M2d macrophages have been associated with increased vascular endothelial growth factor and IL-10 expression and have been proposed to contribute to mucosal healing in UC (22). However, single-cell RNA sequencing analyses also indicate that inflammatory mediators, including IL-1β, may be increased in M1 and multiple M2-annotated macrophage subsets in acute and chronic UC, with chronic UC exhibiting a particularly strong polarization toward a pro-inflammatory M1 phenotype (25) (Fig. 1). These macrophage programs establish the inflammatory inputs subsequently linked to TAK1/TAK1-binding protein (TAB)-dependent signal amplification.

Figure 1.

Immune-microbiota feed-forward circuit in ulcerative colitis. Macrophage imbalance, gut microbiota dysbiosis, epithelial barrier disruption and adaptive immune activation contribute to colitis. Pro-inflammatory M1 macrophage activity is associated with increased IL-1β and IL-6 levels, whereas insufficient M2-associated repair signals, including IL-4/IL-13 and IL-10, weaken mucosal resolution. Microbiota dysbiosis reduces SCFA levels, enhances TLR and NLRP3 inflammasome-related signaling and increases IL-1β and IL-18 levels, thereby contributing to intestinal barrier disruption. Barrier injury allows luminal antigens to activate APCs, promoting Th1 and Th17 responses through IL-12 and IL-23 signaling, respectively. IFN-γ, TNF-α, IL-17 and IL-22 further amplify epithelial damage and sustain colitis. Red upward and downward arrows indicate increases and decreases, respectively, and thick red arrows indicate progression toward epithelial injury and colitis. Black arrows indicate the direction of the indicated relationships. Red plus signs indicate the combined contribution of the three pathways. IL, interleukin; SCFA, short-chain fatty acid; TLR, Toll-like receptor; NLRP3, NOD-like receptor family pyrin domain containing 3; APC, antigen-presenting cell; Th, T helper; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α.

Microbial dysbiosis and innate immune activation

UC is consistently associated with gut microbiota dysbiosis, which is characterized by reduced microbial diversity, depletion of beneficial commensals and expansion of potential pathobionts (26,27). In patients with UC, metagenomic analyses have identified reduced abundance of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii, together with broader reductions in beneficial Firmicutes and Lactobacillus and expansion of Proteobacteria, notably Enterobacteriaceae, and certain Enterococcus species (26-29). This compositional shift may disrupt barrier integrity and immune homeostasis (27).

Reduced levels of short-chain fatty acids, particularly butyrate, weaken mucosal integrity and enhance the activation of pro-inflammatory pathways, including NF-κB and inflammasome signaling (28,30-34). Concurrently, Gram-negative Enterobacteriaceae, particularly Escherichia coli and Klebsiella species, can increase luminal levels of LPS, thereby activating TLR4 on macrophages and dendritic cells and amplifying inflammation (27,35). Mucin-degrading bacteria, including Ruminococcus gnavus and Ruminococcus torques, can further erode the mucus barrier, increasing epithelial exposure to microbial products (36). Since microbial products, including LPS, engage TLR pathways upstream of TAK1, dysbiosis also provides a receptor-level route through which the microbiota can influence NF-κB and MAPK activation (Fig. 1).

Immune signaling crosstalk in UC

UC arises from a self-sustaining interplay between innate and adaptive immunity. A breach of the epithelial barrier permits microbial antigens to access mucosal antigen-presenting cells (APCs), notably macrophages and dendritic cells, which release IL-12 and IL-23 to drive CD4⁺ T-cell polarization toward T helper 1 (Th1) and T helper 17 (Th17) phenotypes, respectively (37-39). Th1 cells produce IFN-γ and TNF-α, activating M1 macrophages and promoting epithelial injury, whereas Th17 cells secrete IL-17, IL-21 and IL-22, recruiting neutrophils, impairing barrier function and amplifying inflammation (40-44). In addition, innate lymphoid cells (ILCs), including ILC1 and ILC3, respond to IL-12 and IL-23, promoting IFN-γ and IL-17 production (45,46). Several of these cytokine receptor and pattern recognition receptor pathways converge on TAK1-containing complexes, providing the signaling context for the cell-specific TAK1 functions discussed below (47,48) (Fig. 1). UC can also include an atypical Th2-like response in which non-classical CD1d-restricted natural killer T cells produce IL-13; this differs from a conventional allergen-driven Th2 response (49).

The UC T-cell response is therefore better described as including atypical Th2-like and Th17 components rather than a uniform conventional Th2 program; contemporary evidence emphasizes Th17 cells as particularly pathogenic (49-51). IL-17 and IL-22 disrupt tight junctions, and neutrophil influx, driven by IL-17-induced chemokines, leads to the release of proteases and reactive oxygen species, thereby exacerbating mucosal injury (52-55). Th1-derived IFN-γ promotes M1 polarization and cytotoxicity (56). Under homeostatic conditions, regulatory T cells (Tregs) and IL-10/TGF-β restrain such responses (57,58); however, in UC, Tregs are reduced or dysfunctional, and monocyte-to-IL-10^high macrophage differentiation is impaired, tipping the balance toward inflammation (59-61).

Humoral immunity further contributes to the inflammatory loop (62). Patients with UC display aberrant IgG responses to commensals, in contrast to homeostatic IgA dominance (63-65). Commensal-reactive IgG forms immune complexes that engage Fcγ receptors on macrophages, inducing NOD-like receptor family pyrin domain containing 3 inflammasome activation and increased IL-1β release (66,67). IL-1β amplifies Th17 responses in T cells and ILCs (68,69). Consequently, dysregulated B-cell responses link microbial recognition to innate and adaptive effector pathways (62,67).

Cytokine crosstalk sustains this inflammatory environment. Macrophage-derived IL-6, IL-1β and IL-23 reinforce pathogenic T-cell phenotypes, and T-cell cytokines, including granulocyte-macrophage colony-stimulating factor and IFN-γ, activate APCs and promote increased pro-inflammatory activity (70-72). Downstream effectors, including TNF-α, IL-17, IFN-γ, IL-1β and leukotrienes, collectively drive epithelial apoptosis, barrier disruption and ulcer formation (53,73-76). Neutrophils further promote tissue injury via elastase, myeloperoxidase and extracellular traps (55,77,78). Collectively, macrophages initiate and perpetuate adaptive immune activation through bidirectional pro-inflammatory interactions with T and B cells. In the absence of sufficient regulatory signals, this network becomes self-amplifying, contributing to the chronic inflammatory state of active UC (Fig. 1). This immune-microbiota loop provides the disease context in which TAK1 can either preserve epithelial survival or amplify inflammatory outputs, depending on the compartment and stage. Autophagy is relevant to this framework because it supports epithelial barrier maintenance, microbial handling and regulation of inflammatory cytokine production in IBD. However, direct evidence that TAK1 controls these autophagic processes in colitis remains limited; autophagy should therefore be viewed here as a parallel homeostatic pathway rather than an established downstream TAK1 output (79).

3. TAK1 functions across barrier control, inflammatory amplification and regulatory restraint in colitis

The immune-microbiota loop outlined above focuses on upstream signaling nodes that translate cytokine and microbial cues into epithelial, myeloid and regulatory outputs. TAK1 is a signaling node downstream of multiple inputs, including TNF/TNFR1, TLRs, IL-1R, selected C-type lectin receptors and antigen receptor pathways. TAK1 relays these signals to NF-κB and MAPKs, including p38, JNK and ERK (80). Therefore, colitis can be viewed as a system shaped by three coupled modules: Epithelial barrier integrity, innate immune amplification and microbiota-linked regulatory restraint. The net effect of TAK1 depends on the cell type, disease stage and preferential routing of signals through downstream pathways, which may explain the seemingly opposite effects of TAK1.

Epithelial TAK1 and barrier fate

Epithelial TAK1 acts as an early gatekeeper that separates a repair-competent barrier trajectory from a death-driven inflammatory one (Fig. 2). Genetic evidence suggests that TAK1 is located upstream of an early bifurcation in intestinal epithelial cells (IECs). IEC-specific TAK1 loss causes spontaneous ileitis or colitis with marked TNFR1-dependent epithelial injury, indicating that TAK1 is required for IECs to resist TNF-rich inflammatory stress without entering cell death programs (14). A recent study supports stage-specific trajectories following epithelial TAK1 loss that are associated with RIPK1 activity and TRADD. TAK1 normally restrains TNFR1-proximal death signaling modules; when these modules are unrestrained, barrier continuity is disrupted and mucosal inflammation worsens (7). This epithelial axis reframes early colitis as a barrier-survival problem, because barrier disruption allows microbial products and luminal antigens to access the lamina propria and sustain innate immune amplification.

Figure 2.

TAK1 functions as an epithelial gatekeeper and a context-dependent inflammatory signaling hub in colitis. (A) In intestinal epithelial cells, TAK1 restrains TNF-TNFR1/proximal RIPK1/TRADD-dependent death signaling to prevent epithelial cell death and preserve barrier integrity. Barrier failure allows luminal microbial products to access the lamina propria, thereby sustaining innate immune amplification. (B) During colitis, ubiquitin modification and scaffold rewiring tune the signaling gain of the TAK1-TAB module: TRIM26 promotes K11-linked TAB1 ubiquitination to enhance TAK1 activation, whereas RNF186-dependent ubiquitination of EPHB2, primarily supported by tumorigenesis-associated evidence, has been proposed to facilitate TAB2 recruitment and reinforce TNF-driven TAK1 signaling. Arrows indicate activation and blunt-ended lines indicate inhibition. TAK1, transforming growth factor β-activated kinase 1; TNFR1, TNF receptor 1; RIPK1, receptor-interacting serine/threonine-protein kinase 1; TRADD, TNFR1-associated death domain protein; TAB, TAK1-binding protein; P, phosphorylation; Ub, ubiquitin; TRIM26, tripartite motif-containing protein 26; RNF186, RING finger protein 186; EPHB2, ephrin type-B receptor 2.

Epithelial TAK1 also participates in epithelial innate immune signaling, which requires strict control of signaling gain. Galectin-3-binding protein suppresses the activation of the epithelial TLR4/TAK1/NF-κB pathway. Galectin-3-binding protein deficiency increases pathway activity and aggravates dextran sulfate sodium (DSS)-induced colitis. These results support a model in which IECs become an autonomous source of inflammatory mediators when TAK1 output is insufficiently constrained (81). Sinapic acid has been proposed to bind TAK1 and suppress TAK1-mediated inflammatory responses. Sinapic acid also restores tight junction organization and localization, improves barrier function and alleviates colitis phenotypes (82). These observations do not negate the role of TAK1 in epithelial survival. Instead, they highlight a necessary balance: Epithelial TAK1 must support survival and repair while avoiding excessive amplification that converts the epithelium into an inflammatory effector tissue (14,81,82).

Essential epithelial TAK1 outputs for survival and repair remain incompletely defined across models, and those that mainly drive pro-inflammatory transcription in IECs remain difficult to identify. Therefore, pharmacological attenuation of inflammatory epithelial outputs must be evaluated with respect to epithelial survival, tight junction integrity and barrier repair endpoints under TNF-rich conditions.

Cell context-dependent regulation of TAK1-linked inflammatory gain

After barrier injury, TAK1-linked inflammatory amplification has been examined in macrophages, dendritic cells and colorectal epithelial or tumor models rather than within a single myeloid-specific framework. The studies cited below identify two recurring mechanisms, ubiquitin modification of TAB adaptor proteins and scaffold reorganization, but their cellular context must be considered when interpreting their relevance to colitis.

TRIM26-dependent K11-linked TAB1 ubiquitination was examined in mouse peritoneal macrophages and bone marrow-derived macrophages, human THP-1 monocytes and Trim26-deficient mice. TRIM26 loss reduced TLR-induced TNF, IL-6 and IL-12p40 production, diminished TAK1/NF-κB/MAPK activation and attenuated DSS colitis, supporting a macrophage-associated gain-enhancing mechanism (83) (Fig. 2). Conversely, RING finger protein (RNF)99-dependent K48-linked ubiquitination and degradation of TAB2 was demonstrated in primary macrophages and bone marrow chimeras; loss of RNF99 increased TLR-driven cytokine production and worsened DSS colitis, supporting a macrophage-derived inhibitory role on TAK1 signaling (84).

By contrast, the mechanisms described in subsequent studies were established in different cellular contexts. RNF186-dependent ubiquitination of ephrin type-B receptor 2 (EPHB2), TAB2 recruitment and TAK1 activation were demonstrated in colorectal epithelial cells and an azoxymethane/DSS colorectal tumorigenesis model (85). Leucine rich repeat kinase 2 (LRRK2)-dependent suppression of autophagy and enhancement of Dectin-1 immunity were examined predominantly in dendritic cells from patients with Crohn's disease and in mouse colitis; their relevance here is pathway-level rather than evidence for macrophage TAK1 function (86). G protein subunit α i1 (GNAI1)- and GNAI3-mediated downregulation of the GP130/JAK2/TNF receptor-associated factor 6/TAK1/TAB1/IKKβ pathway was investigated in azoxymethane/DSS colitis-associated tumorigenesis using CD11c⁺ immune cells, myeloid-derived suppressor cell analyses and biochemical interaction assays, supporting an immune and tumor-context mechanism rather than a general macrophage pathway (87). Together, these findings support context-dependent TAK1 pathway rewiring across epithelial, dendritic and immune or tumor compartments rather than a uniform myeloid mechanism.

Selective disruption of TAK1 signal transmission may reduce pathology without completely blocking TAK1 function. (R)-STU104 inhibits the protein interaction between TAK1 and mitogen-activated protein kinase kinase 3 (MKK3), reducing downstream p38 signaling and inflammatory injury in experimental colitis, with its efficacy exceeding that of mesalazine under the tested conditions (88). Although (R)-STU104 provides proof of concept for output-selective TAK1 modulation, several translational barriers remain unresolved. These include the need to define oral exposure and colonic tissue distribution, gut-targeted delivery strategies that limit systemic immune suppression, pharmacokinetic/pharmacodynamic relationships in inflamed mucosa, possible off-target or pathway-compensatory effects involving related MAPK modules, including MKK6, and epithelial safety under TNF-rich conditions. Consequently, inhibition of the TAK1-MKK3 protein-protein interaction represents a potential preclinical strategy that requires rigorous compartment-resolved safety evaluation before clinical translation. Increased TAK1 pathway activation has also been reported in IBD tissues and experimental models of IBD. Pharmacological inhibition of TAK1 using 5Z-7-oxozeaenol prevented body-weight loss, reduced disease activity and histopathological injury, decreased inflammatory cell infiltration in the colonic mucosa and lowered pro-inflammatory cytokine production in two murine IBD models (15).

Overall, direct macrophage evidence supports opposing ubiquitin-dependent control of TAK1 gain by TRIM26 and RNF99 (83,84), whereas RNF186/EPHB2, LRRK2 and GNAI1/GNAI3 were examined in epithelial, dendritic or colitis-associated tumor contexts (85-87). These studies therefore define context-dependent TAK1 regulation rather than a single myeloid-specific amplification program. The relative contribution of each mechanism to non-neoplastic UC and its distribution across intestinal cell subsets and disease stages remains uncertain. Any selective TAK1-modulation strategy must also be evaluated against the epithelial safety constraints revealed by IEC-specific TAK1 loss (7,14).

Regulatory and adaptive restraint circuits

Regulatory and repair circuits include context-dependent TAK1 outputs in dendritic cell networks. CD137 signaling in CD11b⁻CD103⁺ dendritic cells activates TAK1 and the AMP-activated protein kinase/peroxisome proliferator-activated receptor-γ coactivator 1α axis. This activation increases retinaldehyde dehydrogenase 2 expression and retinoic acid production. Retinoic acid then induces suppressor of cytokine signaling 3 (SOCS3) expression in other dendritic cell subsets through paracrine signaling. SOCS3 suppresses p38 activation and reduces IL-23 production. These changes alleviate acute colitis (89). This mechanism extends the functional view of TAK1 beyond that of a pro-inflammatory kinase, as a metabolic regulatory circuit can limit IL-23-driven pathogenic inflammation (Fig. 3).

Figure 3.

Context-dependent TAK1 output integrates intestinal homeostasis. (A) The CD137 regulatory circuit is activated in CD11b⁻CD103⁺ DCs. CD137 signaling activates a TAK1/AMPK/PGC-1α axis, driving ALDH1A2/RALDH2 expression and subsequent RA production. RA acts in a paracrine manner on adjacent DC subsets to induce SOCS3, which suppresses p38 activation through negative feedback and reduces pathogenic IL-23 levels, thereby alleviating acute colitis. (B) In a distinct context, p38α-deficient DCs exhibit signal rewiring that preferentially routes the TAK1 output to the MKK4/7-JNK-c-Jun pathway. The resulting enhanced IL-27 production promotes Tr1 responses and activates the ILC3/IL-22 axis, thereby strengthening intestinal barrier protection. On the other hand, enterohemorrhagic Escherichia coli Tir can inhibit TAK1 activation, thereby promoting immune evasion. Arrows indicate activation; T-bars indicate inhibition; dashed arrows indicate paracrine signaling. Red upward and downward arrows indicate increases and decreases, respectively. AMPK, AMP-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator 1α; ALDH1A2/RALDH2, retinaldehyde dehydrogenase 2; RA, retinoic acid; SOCS3, suppressor of cytokine signaling 3; IL, interleukin; MKK, mitogen-activated protein kinase kinase; JNK, c-Jun N-terminal kinase; Tr1, type 1 regulatory T cell; TAK1, transforming growth factor β-activated kinase 1; DC, dendritic cell; ILC, innate lymphoid cell; Tir, translocated intimin receptor.

Downstream signaling can also shape barrier-protection programs. Following p38α suppression, enhanced TAK1/MKK4-7/JNK/c-Jun signaling in p38α-deficient dendritic cells can increase IL-27 production, promote type 1 regulatory T cell (Tr1) responses and strengthen the IL-22 barrier-protection axis (Fig. 3). These changes reduce susceptibility to colitis and colitis-associated cancer (90). Therefore, this finding should be interpreted as a context-specific response to p38α suppression rather than a general TAK1 function in all dendritic cells. Pathogens can counteract protective programs by inhibiting TAK1 activation. The translocated intimin receptor effector of enterohemorrhagic Escherichia coli inhibits TAK1 activation and thereby promotes immune evasion (91). These observations indicate that downstream pathway choice can determine whether TAK1 activation escalates inflammation or supports regulatory repair programs (90,91). The determinants that prompt TAK1 toward regulatory vs. inflammatory programs across dendritic cell subsets remain unclear. TAB-related gain regulation and upstream rewiring may also influence this bias (83,90). System-level mapping is needed to integrate these circuits with epithelial survival requirements and innate immune amplification along a unified disease timeline (14,83,90).

Beyond the regulatory circuits in the myeloid and dendritic cell compartments, the adaptive immune system also relies on TAK1 to exert regulatory restraint. Adaptive immunity provides regulatory capacity that prevents microbiota-driven innate stimulation from progressing to chronic inflammation. T-cell TAK1 is required for normal T-cell development and central Treg generation. TAK1 deficiency in T cells is associated with spontaneous colitis (92). In lymphopenia-associated models of T-cell TAK1 deficiency, colitis is associated with a pronounced loss of TCRαβ⁺ CD8α⁺ intraepithelial lymphocytes, and adoptive transfer of intraepithelial lymphocytes alleviates the disease. The disease depends on the gut microbiota and requires myeloid differentiation primary response 88-mediated innate signaling. These results indicate that commensal-driven innate signals can dominate and sustain inflammation when intraepithelial lymphocyte-based suppression is lost (92). The mechanisms connecting TAK1 to Treg differentiation and intraepithelial lymphocyte development or maintenance at different disease stages remain unclear. The quantitative interactions between adaptive regulatory restraint and myeloid TAK1 amplification also require clarification.

Integrated model, therapeutic implications and perspective

A unified model incorporates cell-type specialization, stage dependence and pathway bias. In IECs, TAK1 primarily acts as a survival and barrier gatekeeper by preventing TNFR1-associated epithelial collapse and restraining RIPK1/TRADD-linked pathology (7,14). In innate immune compartments, macrophage-focused evidence supports opposing regulation of TAK1 inflammatory gain by TRIM26 and RNF99, and stage-resolved studies show later TAK1 activation in non-epithelial inflammatory cells (15,83,84). Related mechanisms in colorectal epithelial, dendritic and colitis-associated tumor contexts should not be generalized as myeloid-specific effects (85-87). In dendritic and adaptive immune cells, TAK1 can support regulatory and repair programs, including retinoic acid- and SOCS3-mediated IL-23 suppression, IL-27-driven Tr1 responses with IL-22-mediated barrier protection and tolerance mechanisms involving Treg and intraepithelial lymphocytes (89-92). Early disease outcomes depend mainly on epithelial survival and barrier integrity, whereas later progression and chronicity depend more on sustained innate amplification and structural reinforcement of TAK1 pathway engagement (7,14,15,83,84).

Therapeutic implications follow from this framework and should be considered as preclinical design principles. First, systemic TAK1 blockade should be approached cautiously, as epithelial TAK1 supports survival under TNF-rich stress (7,14). Second, output-based strategies, including the inhibition of defined protein-protein interactions such as TAK1-MKK3, are preferable to broad kinase suppression when they can reduce pathogenic p38 and NF-κB outputs while sparing epithelial protection (15,88). Third, candidate approaches should be tested under TNF-rich epithelial stress and evaluated simultaneously for epithelial survival, barrier integrity, cytokine output and myeloid activation (7,14,15,83-88). Fourth, local gut delivery should be prioritized to limit systemic immune suppression and to establish colonic exposure, pharmacokinetic and pharmacodynamic relationships and compartment-specific safety.

Biomarker development should also distinguish inflammatory amplification from repair. Candidate biomarkers include epithelial death markers, RIPK1/TRADD activity, NF-κB/MAPK inflammatory signatures, TAB1/TAB2 ubiquitin-modification status, IL-23/IL-27 balance, barrier repair and tight junction markers and microbiota-derived inflammatory cues. These markers could help identify disease stages in which TAK1 activity is predominantly pathogenic and those in which epithelial TAK1 is required for repair and barrier maintenance (7,14,15,83-90).

4. Conclusions

TAK1 should be considered a context-sensitive integrator rather than a uniformly pathogenic kinase in colitis. In epithelial compartments, TAK1 supports survival, barrier integrity and repair during inflammatory stress. In myeloid compartments, TAK1 can amplify NF-κB and MAPK-driven cytokine output, whereas TAK1-dependent routing can also contribute to regulatory restraint in dendritic cells and adaptive immune circuits.

Therefore, the central therapeutic problem is the epithelial safety paradox. Broad TAK1 inhibition may attenuate inflammatory amplification, but it may also weaken the epithelial survival programs required to prevent TNFR1-, TRADD- and RIPK1-linked barrier collapse. This concern is particularly relevant in TNF-rich mucosa, where the same signaling node may separate repair-competent adaptation from death-driven inflammation.

Future studies should move from global TAK1 activity toward compartment-resolved interpretations. Priorities include cell-type-specific TAK1 activity profiling, biomarker development to distinguish amplification from repair and testing output-based inhibitors in TNF-rich environments. Such studies may help translate TAK1 biology from a broad inflammatory target into a precise, stage-aware therapeutic strategy. By integrating immune-microbiota crosstalk with compartment- and stage-resolved TAK1 biology, the present review extends pathway-centered summaries and places the epithelial safety paradox at the center of therapeutic interpretation.

Funding Statement

Funding: This work was supported by the Natural Science Foundation of Jilin Province (grant nos. 20200201607JC and YDZJ202401132ZYTS).

Availability of data and materials

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Authors' contributions

SW and GL contributed to study conceptualization. SW, HD and RL contributed to literature search, data curation and visualization. SW contributed to writing the original draft. HD contributed to revision, manuscript reorganization and scientific editing. HD, SW and GL contributed to reviewing and editing the manuscript. GL supervised the work and acquired funding. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.