Matricellular proteins in immunometabolism and tissue homeostasis

Abstract

Matricellular proteins are integral non-structural components of the extracellular matrix. They serve as essential modulators of immunometabolism and tissue homeostasis, playing critical roles in physiological and pathological conditions. These extracellular matrix proteins including thrombospondins, osteopontin, tenascins, the secreted protein acidic and rich in cysteine (SPARC) family, the Cyr61, CTGF, NOV (CCN) family, and fibulins have multi-faceted functions in regulating immune cell functions, metabolic pathways, and tissue homeostasis. They are involved in immune-metabolic regulation and influence processes such as insulin signaling, adipogenesis, lipid metabolism, and immune cell function, playing significant roles in metabolic disorders such as obesity and diabetes. Furthermore, their modulation of tissue homeostasis processes including cellular adhesion, differentiation, migration, repair, and regeneration is instrumental for maintaining tissue integrity and function. The importance of these proteins in maintaining physiological equilibrium is underscored by the fact that alterations in their expression or function often coincide with disease manifestation. This review contributes to our growing understanding of these proteins, their mechanisms, and their potential therapeutic applications.

INTRODUCTION

Matricellular proteins are non-structural extracellular matrix (ECM) components that play a crucial role in modulating cell-matrix interactions and mediating a multitude of biological processes (1). Although they are not involved in physical formation of the ECM, they can act as regulators of cell behavior, offering a unique perspective on tissue development, homeostasis, and disease.

The term “matricellular” was introduced in the 1990s by Paul Bornstein. Since then, it has been expanded to include a variety of protein families such as thrombospondins (TSPs), tenascins (TNs), osteopontin (OPN), the secreted protein acidic and rich in cysteine (SPARC) family, the Cyr61, CTGF, NOV (CCN) family, and the fibulins (2, 3). Expression levels of these proteins are typically upregulated during development, tissue repair, and in response to stress or injury, further reinforcing their critical roles in modulating biological processes (4).

In recent years, immunometabolism, which explores the intersection of immune responses and metabolic processes, has gained considerable attention (5, 6). Matricellular proteins have been implicated in immunometabolism as they play crucial roles in modulating immune cell function, driving metabolic adaptation, and mediating inflammatory responses. Furthermore, dysregulation of these proteins is associated with numerous pathological conditions such as inflammation, fibrosis, obesity, cardiovascular diseases, and cancer, rendering them potential therapeutic targets (1, 7, 8).

Given the breadth and complexity of matricellular protein functions, this review aims to provide a comprehensive overview of their roles in immunometabolism and tissue homeostasis, with a focus on their pathological implications.

BIOLOGY OF MATRICELLULAR PROTEINS

Matricellular proteins serve as crucial mediators of cell-matrix interactions, affecting cellular behavior. Although they are not major structural components of the ECM, matricellular proteins are indispensable for fine-tuning the cellular microenvironment. They contribute to a wide variety of biological processes such as cellular adhesion, migration, and differentiation (1). Each matricellular protein has a unique structure and function. Collectively, they contribute to the regulation of cell-matrix interactions and intracellular signaling pathways. This section presents a deeper understanding of several representative matricellular proteins, including TSPs, TNs, OPN, SPARC family, CCN family, and fibulins (Table 1).

Table 1.

Summarized biological functions of matricellular proteins and their subtypes

Matricellular proteins	Subtypes of matricellular proteins	Cell/tissue	Biological functions
TSPs	TSP-1	Endothelial cell	Increases cell apoptosis (16)
			Modulates cell adhesion (19)
			Modulates cell migration (23)
		Osteoclast	Promotes differentiation (25)
	TSP-2	Endothelial cell	Suppresses angiogenesis (24)
TNs	TNC	Endothelial cell	Increases cell migration (41)
		Astrocyte	Promotes cell proliferation and migration (42)
		Osteosarcoma	Promotes cell migration and lung metastasis (43)
		Neural progenitor cell	Regulates cell differentiation (44)
		Mesodermal cell	Promotes cell differentiation (45)
	TNX	Bovine foetal tissue	Increases collagen fibrillogenesis (46)
OPN	OPN	Osteoclast	Promotes cell migration (59)
		Breast cancer cell	Induces cell migration and invasion, inhibits cell apoptosis (60)
		Macrophage	Increases cell migration (61)
			Inhibits macrophage-to-osteoclast differentiation and decrease inflammation (64)
		Gastric cancer cell	Increases cell proliferation, invasion, and migration, inhibits apoptosis (62)
		Cancer cell	Stimulates cancer cell migration (63)
		Adipocyte	Decreases adipogenesis (65)
SPARC family	SPARC	Embryo	Promotes basal lamina maturation (76)
		Endothelial cell	Regulates fibrinolysis and angiogenesis (77)
		Glioma cell	Promotes cell invasion (79)
		Bone	Promotes osteoblast differentiation (81)
	SPARCL1	Endothelial cell	Decreases cell attachment (78)
		Muscle-derived satellite cell	Promotes cell differentiation and migration (80)
CCN family	CCN1	Fibroblast	Promotes cell adhesion (104)
		Endothelial cell	Promotes cell adhesion and migration (98)
	CCN2	Keratinocyte	Promotes cell adhesion and migration (105)
		Chondrocyte	Promotes cell differentiation and proliferation (106)
		Osteoblast	Promotes cell differentiation and proliferation (107)
Fibulins	Fibulin-1	Platelet	Promotes cell adhesion (109)
		Neural crest cell	Promotes cell migration and survival for development (132)
	Fibulin-3	Endothelial cell	Inhibits cell migration (131)
	Fibulin-4	Smooth muscle cells/fibroblast	Promotes development of arterial elastic lamina (133)
	Fibulin-5	Endothelial cell	Inhibits cell migration (131)

TSPs belong to a family of matricellular proteins. There are five TSPs, TSP-1 to TSP-5 coded by separate genes. TSP-1 and TSP-2 have been mainly investigated in the TSP family regarding their biological functions. Multiple cell types are known to produce and secrete TSPs. For example, platelets are releasing TSP-1 upon activation, which subsequently aids in wound healing and inflammation regulation (9). Endothelial cells express TSP-1, influencing processes such as angiogenesis and vascular homeostasis (10). Additionally, macrophages secrete TSP-1, which modulate immune responses in tissue injury (11). Fibroblasts synthesize TSP-2 during tissue repair, influencing fibrosis and tissue integrity (12). As vital matricellular proteins, TSPs are regulated in their expression by various external cues. Transforming growth factor-β (TGF-β) is a key signaling molecule that induces the expression of TSP-1, contributing to the control of tissue remodeling (13). Hypoxia is another crucial trigger and TSP-1 expression is upregulated under hypoxic condition, thereby modulating angiogenesis and tissue repair (14). Furthermore, oxidative stress has been demonstrated to enhance TSP-2 expression, reflecting the protein’s role in response to stress (15). TSPs engage in numerous interactions with diverse molecules, modulating various cellular processes. Cell membrane glycoprotein CD36 is one of the interaction partners. The binding of TSP-1 to CD36 inhibits angiogenesis by inducing endothelial cell apoptosis (16). Another interaction partner is the integrin family of cell adhesion receptors. The interaction between TSPs and integrins such as α3β1 is essential for cell-to-matrix adhesion, migration, and modulation of growth factor signaling (17). TSP-1 affects αvβ3 function by interacting with integrin-associated protein CD47 (18). TSPs also bind to proteoglycans, like syndecan-4, impacting cell adhesion and angiogenesis (19). Additionally, TSP-1’s interaction with TGF-β plays a significant role in the activation of the latent form of TGF-β, which is a crucial mediator in various pathophysiological processes like inflammation and fibrosis (20). TSPs are multifunctional proteins involved in a range of biological processes such as cellular adhesion, migration, and differentiation. TSPs exhibit diversity in their structures, which can influence their functional roles. For instance, TSP-1 and TSP-2 are trimeric, while TSP-3, TSP-4, and TSP-5 are pentameric (21). TSP-1 mediate cellular adhesion by interacting with a variety of cell surface receptors including CD36 and CD47 (16, 22). Migration of cells is a complex process. TSPs play a key role in regulating this process. TSP-1 can modulate the migration of endothelial cells by upregulating metalloproteinase-9 (MMP-9). TSPs inhibits the angiogenesis by changing ECM composition and expression of MMPs (23, 24). TSPs are also critical in cellular differentiation processes. TSP-1 in particular is known to support the differentiation of osteoclasts and Treg cells (25).

Tenascins are a family of matricellular proteins. There are four members of tenasins: tenascin-C, -R, -X, and -W. They are produced by a variety of cell types. Tenascin-C (TNC) is produced by fibroblasts in the stroma of various tumors, and its elevated levels often correlate with tumor aggressiveness (26). Furthermore, in developing and adult nervous tissue, astrocytes and neurons express TNC, implicating its role in neural plasticity (27). Tenascin-R (TNR), predominantly found in the nervous system, is produced by oligodendrocytes and some subsets of neurons, playing a role in regulating neural cell adhesion and neurite outgrowth (28). Tenascin-X (TNX) production is primarily attributed to fibroblasts within the connective tissues, influencing tissue elasticity and structure (29). Tenascin-W (TNW) has been detected in certain types of cancer, suggesting endothelial cells in blood vessels might be its main producers (30). Tenascins respond to an array of external stimuli which modulate their expression levels. For example, cytokines such as TGF-β and TNF-α have been demonstrated to enhance the expression of TNC in fibroblasts, suggesting its involvement in wound healing and inflammatory processes (31, 32). Furthermore, mechanical stress, a key component in tissue remodeling, significantly induces TNC expression in musculoskeletal tissues, pointing to its role in tissue repair and remodeling (33). During brain neural development, nerve growth factor (NGF), augment the production of TNR, highlighting its role in central nervous system (34). The expression of TNX can be induced by brain-derived neurotrophic factor (BDNF) in human endothelial cells, implying its importance in tissue regeneration (35). Given the increased levels of TNW in malignant tumors, bone morphogenic protein (BMP)-2 stimulated the expression of TNW in cells that locate in tumor stroma (36). The tenascins engage in multiple interactions which are pivotal to their diverse biological functions. TNC interacts with fibronectin, thereby influencing cell adhesion and tumor cell proliferation (37). Additionally, TNC has been found to bind with syndecans, modulating cell-matrix adhesions and influencing cell signaling (38). TNR, largely found in the nervous system, interacts with contactin-1, contributing to the modulation of neural cell adhesion and neurite outgrowth (39). While the interaction partners for TNX and TNW are less extensively studied, their interplay with various collagens and integrins in the extracellular matrix is being unraveled, suggesting their roles in tissue structure and integrity (36, 40). Tenascins have been implicated in a variety of biological processes including cellular adhesion, migration, and differentiation. TNC and TNX are among prominent family members contributing to these biological activities. Tenascins, particularly TNC, are recognized as anti-adhesive molecules. They can disrupt adhesion of cells to the extracellular matrix, promoting cell detachment and facilitating cell migration (41). Migration of cells, especially during wound healing and cancer metastasis, is another key cellular process regulated by tenascins (42, 43). Tenascins also play significant roles in cellular differentiation processes. TNC has been implicated in the differentiation of various cell types, including neural progenitor cells and muscle cells (44, 45). TNX, on the other hand, has been associated with differentiation of connective tissues, notably influencing collagen fibrillogenesis (46).

OPN is a multifunctional matricellular protein that plays crucial roles in various physiological and pathological processes. Its name, osteopontin, derived from its initial identification in bone, reflects its critical role in osteogenesis, with osteoblasts and osteoclasts being primary producers (47). However, its expression is not restricted to bone tissues. Many immune cells, including activated T cells, macrophages, and dendritic cells, produce OPN, where it modulates immune responses and inflammatory reactions (48, 49). In the process of wound healing and tissue repair, fibroblasts have been shown to produce OPN (50). Additionally, in pathological contexts such as cancer, tumor cells themselves can upregulate and secrete OPN, promoting tumor progression and metastasis (51). The regulation of OPN expression is intricate, responding to various external stimuli to fulfill its roles in physiological and pathological contexts. Inflammatory cytokines, such as interleukin-1 (IL-1) can enhance OPN expression in dendritic cells, highlighting its involvement in immune and inflammatory responses (52). Hormonal signals, particularly 1,25-dihydroxyvitamin D3 induces OPN expression in osteoblast, linking it to bone metabolism (53). Additionally, growth factors such as TGF-β and platelet-derived growth factor (PDGF) have been identified as upregulators of OPN, indicating its participation in tissue repair (50, 54). OPN exhibits an array of binding interactions that underpin its diverse roles in cellular processes. One of the key interaction partners of OPN is the integrin family. For example, OPN can bind to αvβ1, αvβ3, and αvβ5 in tumor cells (55). Another major binding partner is CD44. The binding of OPN to CD44 variants facilitates migration and invasion of cancer cells, suggesting a potential mechanism by which OPN contributes to tumor progression (56). Calcium binding is another critical interaction for OPN, considering its role in mineralized tissues, and this interaction modulates crystal growth and biomineralization processes (57). Moreover, OPN’s interaction with thrombin creates a cleaved form that exposes cryptic sites, enhancing integrin-binding activity, a process that plays a role in wound healing and tissue remodeling (58). OPN is a multifunctional matricellular protein that can modulate cellular adhesion, migration, and differentiation. OPN has a significant role in cellular adhesion, primarily mediated by its interaction with several integrins such as αvβ3 and α4β1 (59, 60). It can enhance the adhesion of a variety of cells including immune cells, endothelial cells, and tumor cells, contributing to processes such as wound healing, immune response, and tumor metastasis (61, 62). Migration of cells is another process where OPN plays a crucial role. It can stimulate cell migration in various physiological and pathological contexts, including cancer progression (63). Molecular mechanisms of the migration involve OPN-integrin interaction, leading to the activation of downstream signaling pathways such as PI3K/Akt/mTOR pathway (60). Differentiation processes are also influenced by OPN. OPN has been implicated in the differentiation of immune cells, osteoclasts, and adipocytes. It often contributes to pathological conditions such as inflammation, bone diseases, and obesity (64, 65).

The SPARC family includes SPARC (Osteonectin) and other matricellular proteins such as SPARC-like 1 (SPARCL1)/Hevin, and SPARC/osteonectin, cwcv, and kazal-like domains proteoglycan (testican) 1 (SPOCK1) (66). SPARC, a well-investigated member of this family, is produced by various cell types, including osteoblasts, contributing to bone mineralization (67). It is also expressed in fibroblasts, endothelial cells, and certain cancer cells, suggesting its role in wound healing, angiogenesis, and tumor biology (68). SPARCL1 is predominantly found in the brain and is expressed in astrocytes (69). The SPARC family proteins are modulated by a myriad of external signals. For SPARC, TGF-β has been demonstrated as a potent stimulator of its expression in fibroblasts, emphasizing its role in wound healing and fibrosis (70). Furthermore, SPARC expression is elevated by treatment of vascular endothelial growth factor (VEGF) in endothelial cells, implying its involvement in angiogenesis (71). SPARCL1 has been shown to be upregulated in astrocytes in response to injury-induced cues, suggesting its active role in synaptic modifications and neural repair (72). The SPARC family interact with various proteins influencing cellular behavior. SPARC prominently interacts with collagens, including collagen type I, II, III, IV, and V, modulating collagen fibrillogenesis and influencing tissue remodeling (66). It also binds to various integrins such as integrin β1 (73). Additionally, SPARC’s interaction with VEGF hinders angiogenesis, shedding light on its potential anti-tumorigenic properties (74). SPARCL1 forms complexes with the proteoglycan decorin, which is vital for its role in extracellular matrix synthesis and collagen fibril formation (75). These proteins play a critical role in cellular adhesion, migration, and differentiation. Cellular adhesion is largely influenced by the SPARC family. SPARC has been shown to modulate cell-matrix interactions by binding to various ECM proteins such as collagens, vitronectin, and fibrinogen (76, 77). SPARCL1 similarly can inhibit cell adhesion by affecting organization of the ECM (78). In terms of cell migration, SPARC and SPARCL1 can regulate the migratory behavior of various cell types. SPARC influences cell migration by modulating the ECM, activating intracellular signaling pathways and affecting the expression and activity of matrix MMPs (79). Similarly, SPARCL1 influences cell migration by interacting with ECM components and integrins (80). SPARC’s role in differentiation is widely recognized. For example, in bone, SPARC is considered essential for the differentiation of osteoblasts, thereby playing a critical role in bone formation and remodeling (81).

The CCN family (CCN1-6) is a group of cysteine-rich regulatory proteins known to play critical roles in diverse cellular processes. The CCN family was named after the first three members identified, Cyr61 (CCN1), CTGF (CCN2), and NOV (CCN3). It is a group of secreted, cysteine-rich, regulatory proteins. Other members include WISP-1 (CCN4), WISP-2 (CCN5), and WISP-3 (CCN6) (82). CCN1 is produced by a variety of cells, including fibroblasts, endothelial cells, pericytes, and certain cancer cells, playing critical roles in processes like angiogenesis, wound healing, and tumorigenesis (83, 84). CCN2 is prominently synthesized by chondrocytes, fibroblasts, endothelial cells, and vascular smooth muscle cells, highlighting its functions in skeletal development, fibrosis, and vascular biology (85-87). CCN3 is mainly expressed by cells in the vascular system, including vascular smooth muscle cells, as well as certain tumor cells (88, 89). CCN4, CCN5, and CCN6 are expressed in various cells, including those in skeletal tissues and tumors, indicating potential roles in bone biology and oncogenesis (90-92). The CCN family’s expression is influenced by numerous external signals. CCN1 expression is significantly upregulated by growth factors such as PDGF and VEGF, underlining its role in processes like angiogenesis and wound healing (93, 94). CCN2 is upregulated in response to TGF-β in various cell types, especially fibroblasts (95). While CCN3 was identified as a nephroblastoma overexpressed gene, CCN3 has been downregulated by PDGF in mesangial cells of kidney (96). As the WISP means the Wnt1-inducible signaling pathway proteins, CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3) are upregulated in the mouse mammary epithelial cells transformed by Wnt-1 and they are considered to play a pivotal roles in tumorigenesis (97). The CCN proteins are recognized for their ability to interact with a variety of partners. CCN1 has been shown to bind integrins, specifically αvβ3 and α6β1 in endothelial cells (98). CCN2 forms complexes with various molecules, notably the VEGF, modulating angiogenesis, and also with the αvβ3 (99, 100). CCN3 predominantly interacts with integrins like αvβ3 and α5β1 (101). CCN4, CCN5, and CCN6 interact with components of the ECM such as decorin, biglycan, and integrin αvβ3, suggesting their involvement in ECM organization (102, 103). CCN proteins have been widely recognized for their important roles in cellular adhesion, migration, and differentiation. In relation to cellular adhesion, CCN proteins have been found to modulate cell-matrix interactions mainly through binding with various ECM proteins and surface proteins. For example, CCN1 can promote cell adhesion by binding directly to integrins, leading to activation of downstream signaling pathways (104). In terms of cell migration, CCN proteins can act as chemoattractants and induce changes in the cytoskeleton to facilitate migration. Both CCN1 and CCN2 have been reported to promote cell migration in endothelial cells and keratinocytes through their interactions with integrins (98, 105). Finally, CCN proteins contribute to cell differentiation. CCN2 is known for its pivotal role in chondrogenesis and osteogenesis by modulating the differentiation of mesenchymal stem cells into chondrocytes and osteoblasts (106, 107).

The fibulin family comprises seven members: Fibulin-1 to -7. It is another essential group within matricellular proteins (108). They are produced by various cell types, depending on the specific family member and tissue context. Fibulin-1, a widely expressed protein, is expressed in fibroblasts, and smooth muscle cells, playing roles in vascular remodeling and platelet adhesion (109). Fibulin-2 is highly expressed in cardiovascular system, primarily produced by endothelial cells and certain epithelial cells (110, 111). Fibulin-3 is abundantly expressed in epithelial and endothelial cells implicating its role in angiogenesis (112). Expression of fibulin-4 and fibulin-5 is prominent in vascular smooth muscle cells which are integral to elastogenesis (113, 114). Fibulin-6 is prominently expressed in epithelial cells, endothelial cell, and vascular smooth muscle cells (115). Fibulin-7 has been reported to be expressed in endothelial cells, odontoblasts, and chondrocytes in multiple vital tissues (116). The expression of fibulins is sensitive to several external signals. Fibulin-1 expression can be downregulated by TGF-β, a potent regulator of extracellular matrix proteins, particularly in airway smooth muscle cells (117). Meanwhile fibulin-2 expression is enhanced by Angiotensin II together with TGF-β stimulation in cardiac fibroblast, suggesting its role in processes like fibrosis and tissue remodeling (118). Fibulin-3 has its expression increased under pathological conditions, including malignant glioma and cardiac fibroblast with heart failure (119, 120). Fibulin-4 levels are elevated in colon cancer tumors compared to the adjacent normal tissues (121). Fibulin-5 has its expression increased under hypoxic conditions in endothelial cells, suggesting its role in the adaptive survival response (122). Fibulin-6 levels are enhanced in cardiac fibroblasts and fibulin-7 is upregulated in glioblastomas modulating neovascularization (115, 123). The fibulin family interact with partners that orchestrate various cellular functions. Fibulin-1 can bind to ECM proteins, including fibronectin, laminin, and nidogen (124). Fibulin-2 associates with ECM proteins such as aggrecan, versican, and brevican, playing a role in matrix assembly (125). Fibulin-2 also interacts with fibrillin-1, highlighting its role in fiber assembly in some tissues (126). Fibulin-3 binds to elastin precursor, tropoelastin, impacting processes like elastogenesis and tissue remodeling (127). Fibulin-4 also interacts closely with tropoelastin, aiding in the proper assembly of elastic fibers (128). Fibulin-5 binds to elastic fiber components, such as lysyl oxidase-like 1 and fibrillin-1, ensuring correct elastic fiber formation (129). Fibulin-6 can bind to the basement membrane protein nidogen-2 implying an essential role in basement membrane integrity (130). Fibulin-7 interacts with matrix proteins, including fibronectin, dentin sialophosphoprotein, and fibulin-1 (116). Each of these proteins has unique characteristics. However, they share common functions in cellular adhesion, migration, and differentiation. In terms of cellular adhesion, fibulins are crucial as they can facilitate cell-to-ECM interactions. For instance, fibulin-1 can promote cellular adhesion by binding ECM component fibronectin (109). The role of fibulins in cell migration is also well-documented. Fibulin-3 and fibulin-5 can inhibit endothelial cell migration antagonizing angiogenesis (131). Finally, in terms of cell differentiation, fibulin-1 and fibulin-4 play crucial roles in morphogenesis of neural crest-derived structures and elastogenesis, respectively (132, 133).

Overall, these matricellular proteins exert a broad range of regulatory functions on cellular adhesion, migration, and differentiation to respond appropriately to environmental cues. These diverse roles highlight the complexity and versatility of matricellular proteins in tissue homeostasis and disease process.

MATRICELLULAR PROTEINS AND IMMUNOMETABOLISM

Matricellular proteins play a central role in the regulation of immunometabolic processes. The emerging field of immunometabolism investigates the intersection between the immune system and metabolic processes, with matricellular proteins acting as significant contributors. In this review, roles of matricellular proteins in immune and metabolic responses and their possible integration at the systemic level rather than metabolic regulation of immune cell function at the cellular level are mainly described (Table 2).

Table 2.

Summarized roles of matricellular proteins in immunometabolism and tissue homeostasis

Matricellular proteins	Immunometabolism	Tissue homeostasis
TSP-1	Activates pro-inflammatory macrophage via CD47 (134) Increases adipocyte proliferation and inflammation in obesity (135) Induces mitochondrial dysregulation and cell death in T cell (137) Regulates T cell activation through LRP1 signaling (139) Inhibits dendritic cell activation (140)	Inhibits angiogenesis in wound healing and tissue regeneration by binding to CD36 (175) Inhibits angiogenesis by impeding VEGF signaling and matrix metalloproteinases (176) Inhibits wound healing by reducing angiogenesis in transgenic mice (177) Promotes angiogenesis by interacting with α3β1 integrin (17)
TSP-2	Inhibits adipocyte proliferation (136)	Regulates angiogenesis (24) Increases vascular density and accelerates wound healing in KO mice (12, 178)
TSP-5		Regulates structural integrity of cartilage ECM (179)
TNC	Associates with increased inflammation in obese adipose tissue (141) Activates inflammation via TLR4 on macrophage in arthritic joint disease (142) Blocks the migration of T cell infiltration in tumor (143)	Interrupts cell-matrix interaction through inhibiting cell-fibronectin interaction (180) Regulates cell migration during wound healing after myocardial injury (181) Contributes to corneal wound healing by enhancing fibronectin expression (182) Upregulated in newly formed blood vessels for vascular remodeling (183)
TNX		Maintains tissue elasticity, induces hypermobility of joints and hyperelasticity by deficiency (184)
OPN	Activates type 1 T cell immune response (48, 144) Induces migration and inflammation of macrophage via CD44 and integrin receptor (145) Associates with increased inflammation and insulin resistance in obese adipose tissue (8, 146) Induces adipocyte insulin resistance and inflammation in differentiated adipocyte (147) Contributes to progression of hepatic inflammation and fibrosis (149)	Regulates bone formation and resorption by interacting with the αvβ3 integrin receptor on osteoclasts (186) Contributes to skin wound healing by stimulating migration of MSCs (187) Regulates smooth muscle cell activity by inhibiting differentiation in cardiovascular tissues (188) Regulates glial cell activity and modulates phagocytic activity in a brain injury model (189)
SPARC	Upregulated in obese adipose tissue (150) Induces inflammatory response and insulin resistance in obesity and type 2 diabetes (151) Interferes with insulin signaling in adipocyte (152) Inhibits adipogenesis by enhancing beta-catenin signaling (153) Induces adipocyte hypertrophy in HFD-fed KO mice (154) Reduces aging- and obesity-induced weight gain and inflammation in adipocyte KO mice (155, 156) Induces pro-inflammatory macrophages (155, 157)	Regulates development and differentiation of lens cells (190) Contributes to bone mineralization and collagen binding (81) Involved in formation of the dermal ECM and collagen fibrillogenesis (191) Regulates cutaneous wound healing process (192)
SPARCL1		Contributes to synaptic plasticity and neuronal tissue homeostasis (193) Regulates corneal wound healing and fibrosis processes (194)
CCN1	Upregulated in steatosis of NASH patients and obese mice and induces inflammation (158) Induces pro-inflammatory macrophage and recruitment of monotype in inflammatory vasculature (159, 160)	Regulates wound healing and tissue repair, and induces fibroblast senescence by binding integrin α6β1 and heparin sulphate proteoglycans (196)
CCN2	Upregulated in obesity and associates with inflammation (161) Associates with macrophage-mediated inflammation and insulin resistance in adipose tissue (162) Contributes to T cell differentiation and induction of pro-inflammatory Th17 cell responses (163)	Contributes to connective tissue formation and wound healing, recruiting Sox2-expressiing progenitor cells and myofibroblast differentiation (197)
CCN3	Positively associates with obesity in human and upregulated in obese adipose tissue in mouse (164) Inhibits glycolysis in chondrocytes (166)	Regulates wound healing and tissue repair by skin fibroblast adhesion and chemotaxis through integrin receptors (198)
CCN4	Upregulated in obese adipose tissue in mouse and inhibition of adipogenesis through inactivation of PPARγ (167)	Promotes wound healing by modulating proliferation, migration, and ECM expression in dermal fibroblast (199)
Fibulin-1	Upregulated in diabetes and cardiovascular diseases and downregulated by taking antidiabetic drug (168, 169)	Contributes to structuring tissues facilitating cell adhesion by binding to fibronectin (201) Contributes to stiffness with aggrecan modulating vascular and cardiac remodeling (202)
Fibulin-2	Upregulated in obese adipose tissue in mouse (170) Regulates immune dysfunction in bone trauma model (171)	Regulates mineralized bone formation and bone resorption (203)
Fibulin-3	Upregulated in osteoarthritis in obese women (172) Upregulated circulating levels in obese middle-aged individuals (173)	Maintains vascular tissue by acting as a growth factor for arteries and inhibiting MMP-2, MMP-9, and oxidative stress (204)
Fibulin-4		Maintains tissue elasticity by interaction with elastin-cross-linking enzymes (133)
Fibulin-5	Regulates insulin secretion in pancreatic beta cell through glucokinase-mediated signaling (174)

TSPs, especially TSP-1 and TSP-2, have been found to play crucial roles in immunometabolism. TSP-1 can activate CD47 on macrophages, affecting pro-inflammatory IL-1β maturation, a critical process for pathogen-induced and metabolic dysregulation-induced inflammation (134). The involvement of TSPs in lipogenesis is also significant. TSP-1 has capabilities to increase proliferation of adipocytes and uptake of fatty acid by adipocytes. It can also modulate inflammation in adipose tissues. Depletion of TSP-1 can protect mice from diet-induced obesity (135). In contrast, TSP-2 can inhibit adipocyte proliferation. TSP-2 knock-out mice show increased weight gain with large amounts of non-visceral adipose tissues (136). TSP-1 and TSP-2 expression can modulate fat storage and release, affecting metabolic syndromes such as obesity and diabetes. Further, TSP-1’s binding with CD47 can induce mitochondrial dysregulation and T cell death (137). As mitochondria are primary sites of cellular energy production, their regulation by these proteins can affect immune cell activation and differentiation, thus modulating the immune response. TSPs also play a role in modulating angiogenesis and inflammation. It has been shown that TSP-1 can regulate mononuclear cell adhesion and migration, causing vascular inflammation in abdominal aortic aneurysm (138). TSP-1 plays a significant role in immune modulation by influencing the activation and function of various immune cells. It has been demonstrated that TSP-1 can regulate motility, adhesion, and activation of T cells through lipoprotein receptor-related protein (LRP1) signaling, thereby modulating immune responses (139). Moreover, TSP-1 can also inhibit dendritic cell activation in an autocrine manner, thus influencing the nature of the initiation of immune responses (140).

Tenascins are known to have critical roles in tissue repair and inflammation. Their regulation of immunometabolic processes is gaining recognition. TNC, the most extensively studied protein of the tenascin family, has been linked to various pathophysiological processes, including immune regulation and metabolic disorders. For example, elevated TNC expression has been observed in visceral adipose tissues of obese individuals. It has been associated with increased ECM remodeling and inflammation (141). TNC can modulate the activation and function of immune cells. TNC is known as an endogenous activator of toll-like receptor 4 (TLR4) on macrophages. It can mediate inflammatory response in arthritic joint disease (142). It also plays a crucial role in immune cell recruitment. TNC can induce CXCL12 and block the migration of infiltrating T lymphocytes (TIL) in tumor microenvironment (143).

OPN plays a crucial role in the immune system by modulating the function of various immune cells. In T cells, OPN can promote the production of IFN-γ and IL-12, driving type 1 T cell immune responses, respectively (48, 144). In macrophages, OPN is involved in the induction of migration, skewing macrophages toward a pro-inflammatory phenotype by interacting with CD44 and integrin receptor (145). In the context of immunometabolism, OPN’s role in adipose tissue inflammation and insulin resistance has been well documented. OPN is upregulated in adipose tissues during obesity. It contributes to the recruitment of pro-inflammatory macrophages, leading to chronic low-grade inflammation and insulin resistance (8, 146). Furthermore, OPN can directly interfere with insulin sensitivity in human differentiated adipocytes, inducing insulin resistance and inflammatory signaling (147). In addition, high levels of OPN have been observed in human atherosclerotic lesions of the aorta (148). Another noteworthy role of OPN in immunometabolism is its involvement in hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). A previous study has shown that OPN expression is increased in these conditions and that OPN contributes to the progression of hepatic inflammation and fibrosis (149).

Roles of SPARC family proteins in immunometabolism have increasingly become an area of focus, especially regarding inflammation, tissue remodeling, and metabolic diseases. Among the SPARC family members, SPARC has been studied extensively. It has been identified as being highly expressed in adipose tissues, particularly under conditions of obesity (150). SPARC contributes significantly to inflammatory response and insulin resistance associated with metabolic disorders such as obesity and type 2 diabetes (151). SPARC’s interaction with insulin signaling has been identified as a critical point of impact. Studies have shown that SPARC can interfere with insulin signaling pathways in adipocytes, leading to a decrease in insulin sensitivity and contributing to systemic insulin resistance, a key feature of metabolic syndrome and type 2 diabetes (152). Moreover, SPARC has been implicated in the regulation of adipogenesis, a process by which pre-adipocytes mature into adipocytes. It has been demonstrated that SPARC can inhibit adipogenesis by enhancing the signaling of beta-catenin, a central player in the Wnt signaling pathway, and the activated Wnt signaling negatively regulates adipocyte differentiation (153). In animal studies, SPARC-deficient mice exhibited enlarged fat pad size and adipocyte hypertrophy upon high-fat diet feeding compared to wild-type mice, suggesting a potential role for SPARC in lipid mobilization (154). Furthermore, SPARC critically influences immunometabolism in aging. Adipocyte-specific SPARC depletion in mice alleviated weight gain and fat mass increase during obesity and aging. Such effects enhanced health span, improved metabolic functions such as insulin sensitivity and glucose tolerance, and reduced inflammation (155, 156). SPARC is also involved in the modulation of inflammatory responses. It has been reported to influence macrophage polarization, thus affecting the balance between pro-inflammatory and anti-inflammatory responses (155, 157).

Recently, an emergent role of the CCN family in immunometabolism, an interface between immune responses and metabolic processes, has come to light. CCN1 is highly expressed in steatosis of NASH (non-alcoholic steatohepatitis) patients and hepatocytes of obese mice (158). Upregulation of CCN1 worsened steatosis and inflammation of NASH mouse model. In addition to its effects on metabolic dysregulation, CCN1 can contribute to the recruitment and activation of immune cells. CCN1 treatment induced pro-inflammatory M1 murine macrophages. CCN1 was responsible for recruitment of Ly6C^low monocytes in inflammatory vasculature (159, 160). These might link immune response, inflammation, and metabolic control. CCN2, a protein implicated in tissue remodeling and fibrosis, shows increased expression in the context of obesity, which is characterized by chronic low-grade inflammation (161). In adipose tissue macrophages, CCN2 upregulation is associated with inflammation and fibrosis, subsequently leading to metabolic dysregulation including insulin resistance (162). C-terminal module of CCN2 also contributes to the differentiation of T cells and induces pro-inflammatory Th17 cell responses, further establishing its role in immune interactions (163). CCN3 plasma levels are positively associated with obesity in human and expression of CCN3 in adipose tissues of high-fat diet fed obese mice is increased (164). CCN3 knockout mice were protected from obesity, insulin resistance, and adipose tissue macrophage-derived inflammation (165). Moreover, there is evidence to suggest CCN3’s involvement in metabolic processes. CCN3 expression was induced by inhibition of glycolysis in chondrocytes, suggesting metabolic regulation of CCN3 (166). CCN4 has been implicated in adipocyte differentiation that is a key aspect of metabolism. CCN4 was upregulated in obese mice models. The increase of CCN4 inhibited adipogenesis through inactivation of PPARγ (167).

In the context of immunometabolic processes, fibulin family’s role is becoming increasingly apparent. Fibulin-1, the first identified member of the fibulin family, has been extensively studied for its role in tissue integrity maintenance. In fact, increased plasma fibulin-1 has been associated with diabetes and cardiovascular diseases. Taking antidiabetic drug metformin attenuated the increase of fibulin-1 levels in type 2 diabetes patients (168, 169). Similarly, fibulin-2 has also been implicated in immunometabolic processes. Increased expression of fibulin-2 has been noted in white adipose tissues of a mouse model in the context of obesity (170). Furthermore, fibulin-2 has been shown to regulate immune dysfunction in bone trauma mouse model, further suggesting a potential role in immune responses (171). Fibulin-3 fragments’ serum levels were associated with osteoarthritis in obese women (172). Increased levels of circulating fibulin-3 are associated with obesity in middle-aged individuals (173). Fibulin-5 expression in pancreatic beta cell is responsible for glucose-stimulated insulin secretion through glucokinase-mediated signaling (174), which is pivotal for maintaining metabolic homeostasis.

In summary, matricellular proteins exhibits a growing importance in the context of immunometabolism (Fig. 1). Comprehensive research is required to elucidate the molecular mechanisms underlying their roles in this intertwined system of immune and metabolic regulation.

Fig. 1.

The interplay of matricellular proteins and immunometabolism. Matricellular proteins play diverse and intricate roles in the field of immunometabolism. The schematic diagram demonstrates the influence of six major matricellular proteins: thrombospondins (TSPs), tenascins (TNs), osteopontin (OPN), SPARC family, CCN family, and the fibulin family. They are involved in crucial metabolic processes, including glucose metabolism, lipid metabolism, and insulin signaling. These proteins also influence the immune response by activating specific immune cell types, such as macrophages, T cells, and dendritic cells, and inducing the recruitment of monocytes. In obesity and NAFLD, the matricellular proteins contribute to immunometabolic regulation in adipose tissue and liver, respectively, which represents the complex interplay and regulatory mechanisms of matricellular proteins within the immune and metabolic systems.

MATRICELLULAR PROTEINS IN TISSUE HOMEOSTASIS

Matricellular proteins play crucial roles in maintaining tissue homeostasis by modulating cell-ECM interactions, cell behavior, and signaling pathways. These proteins can modulate a variety of cellular functions, including cell proliferation, adhesion, migration, and differentiation, thereby maintaining the normal structure and function of various tissues (2).

TSP-1 is a well-known inhibitor of angiogenesis, a critical process in wound healing, tissue regeneration, and various pathological conditions. It exerts its function by binding to the CD36 receptor on endothelial cells, inhibiting their migration, proliferation, and survival (175). Moreover, TSP-1 can impede VEGF signaling and the action of matrix metalloproteinases, thereby inhibiting degradation of the extracellular matrix and reducing angiogenesis (176). TSP-1 can inhibit wound healing process by reducing angiogenesis in TSP-1 overexpressing transgenic mice (177). Interestingly, TSP-1 is not uniformly anti-angiogenic. It can promote angiogenesis by interacting with α3β1 integrin under specific circumstances (17). Other members of the TSP family also play vital roles in tissue homeostasis. For instance, TSP-2, similar to TSP-1, can regulate angiogenesis. It is essential for proper wound healing and tissue repair. TSP-2 null mice show increased vascular density and accelerated wound healing (12, 178). TSP-5 (also known as COMP) contributes to maintaining cartilage homeostasis by regulating structural integrity of the cartilage extracellular matrix crucial for joint function (179).

TNC is primarily expressed in the ECM during embryonic development, inflammation, wound healing, and tumorigenesis. TNC can modulate cell behavior by interrupting cell-matrix interactions, primarily by inhibiting the binding of cells to fibronectin (180). Furthermore, TNC can influence cell migration during wound healing after myocardial injury. It plays a critical role in corneal wound healing by enhancing fibronectin expression (181, 182). Additionally, TNC is involved in angiogenesis. It has been observed that TNC is highly expressed in newly formed blood vessels, indicating its potential role in vascular remodeling, an essential aspect of tissue homeostasis (183). Tenascin-X is widely distributed in connective tissues. It is crucial for maintaining tissue elasticity. Deficiencies in TNX can result in hypermobility of joints and hyperelasticity of the skin, which are characteristic symptoms of the Ehlers-Danlos syndrome (184).

OPN, also known as secreted phosphoprotein 1 (SPP1), is a multifunctional matricellular protein involved in diverse biological processes. OPN plays an instrumental role in maintaining tissue homeostasis through its involvement in cell adhesion, migration, immune response modulation, and ECM remodeling (185). One of the primary sites of OPN activity is the bone tissue, where it is involved in the homeostatic balance between bone formation and resorption. By interacting with the αvβ3 integrin receptor on osteoclasts, OPN can promote cell adhesion, migration, and survival, thereby driving bone resorption (186). In addition to its role in bone homeostasis, OPN has a critical function in the wound healing process. It can stimulate migration and differentiation of mesenchymal stem cells (MSCs) during skin wound repair (187). Moreover, in cardiovascular tissues, OPN has a profound impact on tissue homeostasis as it regulates the activity of vascular smooth muscle cells by inhibiting differentiation and modulates inflammatory responses by inducing accumulation of mononuclear cells (188). In the central nervous system, OPN can influence glial cell activity and modulate phagocytic activity in a brain injury model, contributing to neurological homeostasis (189).

SPARC is widely expressed in various tissues. It exerts its biological effects mainly through interactions with the extracellular matrix and various cell surface receptors (66). SPARC plays a critical role in the development and differentiation of lens cells (190). SPARC, also referred to as osteonectin, plays a crucial role in bone mineralization and collagen binding, thereby having a significant influence on the integrity and function of various tissues. SPARC-deficient mice demonstrate a decreased bone formation, suggesting that SPARC is essential for controlling osteoblast and osteoclast activity (81). SPARC is also important for maintaining skin homeostasis. It is involved in the formation of the dermal ECM. It can also regulate collagen fibrillogenesis. SPARC knockout mice display thinner skin with a disorganized ECM and collagen fibrils, emphasizing its vital role in skin homeostasis (191). Furthermore, SPARC is involved in regulation of cutaneous wound healing process (192). SPARCL1 (Hevin), also known as hevin, has been shown to be involved in tissue remodeling and homeostasis. SPARCL1 has demonstrated involvement in synaptic plasticity, a mechanism essential for neuronal tissue homeostasis. SPARCL1-deficient mice display impaired synaptic plasticity, indicating a critical role in maintaining synaptic homeostasis (193). Moreover, hevin has been identified as a key regulator of corneal wound healing and fibrosis processes intimately tied to tissue homeostasis (194).

CCN family proteins can affect cell-matrix interactions, directly influencing cell behavior and extracellular matrix assembly (195). For instance, CCN1 (CYR61) regulates cell adhesion and migration in a tissue-dependent manner, facilitating wound healing and tissue repair and inducing fibroblast senescence by binding to integrin α6β1 and heparin sulphate proteoglycans (196). CCN2 (CTGF), another member of the CCN family, has been well-studied. It is known to play a central role in tissue repair and fibrosis. CCN2 is essential for connective tissue formation and wound healing, mediating recruitment of Sox2-expressing progenitor cells and myofibroblast differentiation (197). CCN3 (NOV) has been shown to regulate skin fibroblast adhesion and chemotaxis through integrin receptors, which are critical to wound healing and tissue repair processes (198). CCN4 (WISP-1) also contributes to maintaining tissue homeostasis. CCN4 has been found to be upregulated during tissue injury. Previous studies have suggested that CCN4 plays a role in promoting wound healing by modulating proliferation, migration, and ECM expression in dermal fibroblast (199).

The fibulin family proteins contribute to an array of biological functions that underpin tissue integrity, including cell adhesion, migration, proliferation, and differentiation (200). Fibulin-1 facilitates cell adhesion by binding to other ECM components such as fibronectin, thereby enabling structuring of tissues (201). Fibulin-1 has been considered to play a pivotal role in aortic stiffness with aggrecan that modulate the vascular and cardiac remodeling (202). Fibulin-2 contributes significantly to tissue homeostasis. Its influence is particularly prominent within the skeletal system, where it supports tissue development and homeostasis. Genetic deletion of fibulin-2 in murine models leads to enhanced mineralized bone formation and decreased bone resorption (203). Fibulin-3 has a role in the maintenance of vascular tissues. In a hypertensive vascular model, fibluin-3 is considered as a growth factor for arteries. It inhibits MMP-2, MMP-9, and oxidative stress (204). Fibulin-4 play crucial roles in maintaining tissue elasticity by interaction with elastin-cross-linking enzyme (133).

Collectively, matricellular proteins play essential roles in tissue homeostasis across different tissue types (Fig. 2). They contribute to maintaining structural integrity and cellular functions. Dysregulations in their expression or function often result in tissue-specific pathologies, including cancers and fibrosis (205, 206).

Fig. 2.

The role of matricellular proteins in tissue homeostasis. Matricellular proteins maintain tissue homeostasis across various tissue types. The schematic diagram represents the impact of matricellular proteins on essential processes in different tissue types, such as blood vessels, eyes, skin, heart, bone, and brain. These processes include tissue remodeling, tissue repair, angiogenesis, and wound healing, all of which significantly contribute to maintaining tissue homeostasis. The matricellular proteins play different roles in various tissues and contribute to maintaining the equilibrium of the body’s internal environment.

CONCLUSION

The role of matricellular proteins in regulating cell function, tissue homeostasis, and immunometabolism is becoming increasingly evident. These diverse groups of matricellular proteins, including TSPs, TNs, OPN, SPARC family, CCN family, and the fibulin family, play crucial roles in maintaining dynamic interactions between cells and their microenvironment.

Our understanding of the crucial role of matricellular proteins in immunometabolism has grown significantly. They contribute to complex regulation of immune cell behavior and function, including recruitment, activation, and differentiation. Matricellular proteins also exert direct and indirect effects on systemic and cellular metabolism, influencing energy homeostasis and contributing to the fine-tuning of immune responses.

In addition, matricellular proteins play key roles in maintaining tissue homeostasis, influencing processes such as cell adhesion, proliferation, migration, and ECM organization. Any dysregulation in these processes can lead to a wide range of pathologies, further emphasizing the importance of understanding roles of matricellular proteins in tissue homeostasis.

The involvement of matricellular proteins in various pathological conditions such as metabolic disorders, cancer, fibrosis, and inflammatory diseases makes them promising therapeutic targets. Strategies aiming for modulating the activity of these proteins could be beneficial in treating a range of diseases.