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Chimeric galectin-3 and collagens: Biomarkers and potential therapeutic targets in fibroproliferative diseases

2022; Elsevier BV; Volume: 298; Issue: 12 Linguagem: Inglês

10.1016/j.jbc.2022.102622

1083-351X

Pratima Nangia‐Makker, Victor Hogan, Vitaly Balan, Avraham Raz,

Peptidase Inhibition and Analysis

Fibrosis, stiffening and scarring of an organ/tissue due to genetic abnormalities, environmental factors, infection, and/or injury, is responsible for > 40% of all deaths in the industrialized world, and to date, there is no cure for it despite extensive research and numerous clinical trials. Several biomarkers have been identified, but no effective therapeutic targets are available. Human galectin-3 is a chimeric gene product formed by the fusion of the internal domain of the collagen alpha gene [N-terminal domain (ND)] at the 5′-end of galectin-1 [C-terminal domain (CRD)] that appeared during evolution together with vertebrates. Due to the overlapping structural similarities between collagen and galectin-3 and their shared susceptibility to cleavage by matrix metalloproteases to generate circulating collagen-like peptides, this review will discuss present knowledge on the role of collagen and galectin-3 as biomarkers of fibrosis. We will also highlight the need for transformative approaches targeting both the ND and CRD domains of galectin-3, since glycoconjugate binding by the CRD is triggered by ND-mediated oligomerization and the therapies targeted only at the CRD have so far achieved limited success. Fibrosis, stiffening and scarring of an organ/tissue due to genetic abnormalities, environmental factors, infection, and/or injury, is responsible for > 40% of all deaths in the industrialized world, and to date, there is no cure for it despite extensive research and numerous clinical trials. Several biomarkers have been identified, but no effective therapeutic targets are available. Human galectin-3 is a chimeric gene product formed by the fusion of the internal domain of the collagen alpha gene [N-terminal domain (ND)] at the 5′-end of galectin-1 [C-terminal domain (CRD)] that appeared during evolution together with vertebrates. Due to the overlapping structural similarities between collagen and galectin-3 and their shared susceptibility to cleavage by matrix metalloproteases to generate circulating collagen-like peptides, this review will discuss present knowledge on the role of collagen and galectin-3 as biomarkers of fibrosis. We will also highlight the need for transformative approaches targeting both the ND and CRD domains of galectin-3, since glycoconjugate binding by the CRD is triggered by ND-mediated oligomerization and the therapies targeted only at the CRD have so far achieved limited success. The extracellular matrix (ECM) is the noncellular scaffold structure present within all tissues and organs, composed mainly of proteoglycans and fibrous proteins. It is crucial for tissue morphogenesis, differentiation, and homeostasis. ECM can be divided into basement membrane and interstitial matrix. The basement membrane, which functions as a scaffold for epithelial and endothelial cells, is composed of collagen type IV, laminin, nidogen (enactin), and perlecan. The major component is collagen type IV, constituting about 50% of all basement membrane proteins. Laminin is the major noncollagenous component of the basement membrane. The interstitial matrix, mainly produced by fibroblasts and composed of collagen I, III, V, and VI, fibronectin, and proteoglycans makes up the majority of ECM in the body. These components together assemble in a highly cross-linked network, with great functional and compositional variations allowing rapid diffusion of certain small molecules (reviewed in (1Genovese F. Karsdal M.A. Protein degradation fragments as diagnostic and prognostic biomarkers of connective tissue diseases: understanding the extracellular matrix message and implication for current and future serological biomarkers.Expert Rev. Proteomics. 2016; 13: 213-225Crossref PubMed Scopus (20) Google Scholar)). Tissue injury knocking out epithelial and endothelial cells and exposure of basement membrane results in an influx of inflammatory cells, such as macrophages and neutrophils into the damaged site. These cells secrete proteases to degrade the basement membrane and release the fragments of component proteins into circulation. To repair the basement membrane, the activated fibroblasts secrete new proteins to substitute the degraded proteins (Fig. 1A). This results in wound healing. In case of chronic inflammation, the deeper tissues including the interstitial layer of ECM are exposed and get damaged. Several inflammatory cytokines including the interleukins (2Nikolic-Paterson D.J. Main I.W. Tesch G.H. Lan H.Y. Atkins R.C. Interleukin-1 in renal fibrosis.Kidney Int. Suppl. 1996; 54: S88-90PubMed Google Scholar, 3O'Reilly S. Ciechomska M. Cant R. Hugle T. van Laar J.M. Interleukin-6, its role in fibrosing conditions.Cytokine Growth Factor Rev. 2012; 23: 99-107Crossref PubMed Scopus (60) Google Scholar) and members of transforming growth factor-β (TGF-β) (4Wu N. Meng F. Invernizzi P. Bernuzzi F. Venter J. Standeford H. et al.The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor-beta1 biliary secretion in mice.Hepatology. 2016; 64: 865-879Crossref PubMed Scopus (68) Google Scholar, 5Walton K.L. Johnson K.E. Harrison C.A. Targeting TGF-beta mediated SMAD signaling for the prevention of fibrosis.Front. Pharmacol. 2017; 8: 461Crossref PubMed Scopus (298) Google Scholar) secreted by platelets, endothelial cells, smooth muscle cells, and macrophages act on fibroblasts to induce proliferation and differentiation. The differentiated fibroblasts continue to secrete proteins leading to disproportionate accumulation of collagen in the interstitial space, causing scarring of the affected organ (1Genovese F. Karsdal M.A. Protein degradation fragments as diagnostic and prognostic biomarkers of connective tissue diseases: understanding the extracellular matrix message and implication for current and future serological biomarkers.Expert Rev. Proteomics. 2016; 13: 213-225Crossref PubMed Scopus (20) Google Scholar) (Fig. 1B). Galectin-3 is a profibrotic molecule regulating the functions of macrophages and fibroblasts in response to inflammation. It was shown that increased galectin-3 expression further activates myofibroblasts leading to wound scarring and is thus implicated in inflamed organ's 'fibrosis'(Fig. 1). On the other hand, its deficiency leads to reduced fibrotic response. The abnormal remodeling of the ECM is related to a plethora of fibroproliferative diseases of various organs including heart, liver, lung, kidneys, skin, and some systemic disorders such as systemic sclerosis, atherosclerosis, and cystic fibrosis (Fig. 2) and is responsible for nearly 45% of all deaths (6Wynn T.A. Fibrotic disease and the T(H)1/T(H)2 paradigm.Nat. Rev. Immunol. 2004; 4: 583-594Crossref PubMed Google Scholar). The mechanism of fibrosis is similar in various organs as all epithelial tissues such as skin, digestive tract, pulmonary organs, genitourinary tracts, and endothelial cells of blood vessels, as well as mesothelial cells in the body cavities, are lined by ECM (7Mak K.M. Mei R. Basement membrane type IV collagen and laminin: an overview of their biology and value as fibrosis biomarkers of liver disease.Anat. Rec. (Hoboken). 2017; 300: 1371-1390Crossref PubMed Scopus (129) Google Scholar, 8Vracko R. Basal lamina scaffold-anatomy and significance for maintenance of orderly tissue structure.Am. J. Pathol. 1974; 77: 314-346PubMed Google Scholar). In recent years, fibroproliferative process has been the focus of interest as a candidate for disease intervention. The noninvasive method of detecting fibrosis is by analyzing the levels of circulating biomarkers. Several biomarkers have been studied including collagen-related peptides, matrix metalloproteases (MMPs), tissue inhibitors of metalloproteases, selected miRNAs, galectin-3, and several noncollagen-related peptides. Among these, collagen peptides and galectin-3 appear to be most promising as reflecting combined effects of injury, inflammation, and fibrosis. In this review, we have selected the liver, heart, and lung as representative organs of fibroproliferative diseases, and we will discuss the current knowledge on these two proteins and their peptides as biomarkers of fibrosis and disease progression and value of galectin-3 as a therapeutic target. Collagens are a superfamily of 28 members comprising the most abundant proteins in humans. The common feature of all family members is a triple helix structure made up of three polypeptide chains, which can either be homotrimers (3 identical α chains) or heterotrimers (nonidentical α chains) and are of variable lengths in different members. Collagens are characterized by their capacity to form supramolecular assemblies (9Karsdal M.A. Daniels S.J. Holm Nielsen S. Bager C. Rasmussen D.G.K. Loomba R. et al.Collagen biology and non-invasive biomarkers of liver fibrosis.Liver Int. 2020; 40: 736-750Crossref PubMed Scopus (65) Google Scholar). Based on the supramolecular structure, the collagens can be fibrils, beaded filaments, anchoring fibrils, and networks (10Ricard-Blum S. The collagen family.Cold Spring Harb. Perspect. Biol. 2011; 3: a004978Crossref PubMed Scopus (1045) Google Scholar). Further diversity in the collagen family is due to the several molecular isoforms as well as alternative splicing and alternative promoters. Collagens are synthesized as procollagens and cleaved to mature form. The mature collagens are enzymatically cleaved and released as biologically active fragments (10Ricard-Blum S. The collagen family.Cold Spring Harb. Perspect. Biol. 2011; 3: a004978Crossref PubMed Scopus (1045) Google Scholar). As collagens are an integral part of the ECM, their deregulated cleavage and reassembly play an important role in fibrosis. Circulating collagen fragments (neoepitopes) as biomarkers of the fibrogenic or fibrolytic events in various diseases have been studied extensively. Propeptides, which are released from procollagen as part of the maturing process, reflect the synthetic process, whereas the degradation epitopes, which are released as part of the degradation process reflect the fibrolytic process (9Karsdal M.A. Daniels S.J. Holm Nielsen S. Bager C. Rasmussen D.G.K. Loomba R. et al.Collagen biology and non-invasive biomarkers of liver fibrosis.Liver Int. 2020; 40: 736-750Crossref PubMed Scopus (65) Google Scholar). Various collagen epitopes used as biomarkers have been summarized in Table 1.Table 1Major collagen neo-epitopes used as serum biomarkers for fibroproliferative diseasesSynthesis-related epitopesCollagen typeNameDescriptionAffected organCollagen type IPINPAmino-terminal peptide of procollagen type IHeartPICPC-terminal peptide of procollagen type IHeartCollagen type IIIPIIINPAmino-terminal peptide of procollagen Type IIILiver, heart, and lungPro C3A fragment of N-terminal type III collagenLungCollagen type IVP4NP77S domain of type IV collagenLiverNC-1Carboxy-terminal region of alpha chainLiverCollagen type VIProC6A fragment of C-terminal type VIa3 collagenLungDegradation-related epitopesCollagen typeNameDescriptionAffected organCollagen type ICIMMMP degraded fragment of Collagen type ILungCITPCarboxy terminal telopeptide of collagen IHeartCollagen type IIIC3MMMP degraded fragment of Type III collagenLiver, LungC3AADAMTS degraded fragment of type III collagenLungCollagen type IVC4MMMP degraded fragment of type IV collagenLiverCollagen type VC5MMMP degraded fragment of type V collagenLungCollagen type VIC6MMMP degraded fragment of type VI collagenLung Open table in a new tab Human galectin-3 (LGALS3), a protein of 31Kda (11Raz A. Pazerini G. Carmi P. Identification of the metastasis-associated, galactoside-binding lectin as a chimeric gene product with homology to an IgE-binding protein.Cancer Res. 1989; 49: 3489-3493PubMed Google Scholar, 12Raz A. Carmi P. Raz T. Hogan V. Mohamed A. Wolman S.R. Molecular cloning and chromosomal mapping of a human galactoside-binding protein.Cancer Res. 1991; 51: 2173-2178PubMed Google Scholar), belongs to the galectin gene family of carbohydrate-binding proteins and is the only member that is expressed in vertebrates. All of the galectin family members contain a conserved carbohydrate-binding domain of ∼130 amino acids. Galectins have been divided into three subtypes based on their structure: prototype, tandem repeat, and chimera. Galectin-3 is the only chimera (fused) protein consisting of three distinct structural motifs: a short 12 amino acid N-terminal motif, followed by a long collagen α-like sequence (collagen α) and a C-terminal carbohydrate-binding domain (galectin-1). The short N-terminal motif contains a site of serine6 phosphorylation for controlling the nuclear transport and ligand affinity (13Gong H.C. Honjo Y. Nangia-Makker P. Hogan V. Mazurak N. Bresalier R.S. et al.The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells.Cancer Res. 1999; 59: 6239-6245PubMed Google Scholar). The long and intrinsically disorganized collagen α like proline-rich sequence of about 110 amino acids (ND) is cleavable by MMPs -2, -9, and membrane type 1 MMP at the Ala62-Tyr63 bond, resulting in the generation of a cleaved fragment of 22kD (14Ochieng J. Fridman R. Nangia-Makker P. Kleiner D.E. Liotta L.A. Stetler-Stevenson W.G. et al.Galectin-3 is a novel substrate for human matrix metalloproteinases-2 and -9.Biochemistry. 1994; 33: 14109-14114Crossref PubMed Google Scholar) (Fig. 3). The C-terminal domain (CRD), consisting of about 130 amino acids, is the common domain shared by all galectin family members and is responsible for their lectin activity. Galectin-3 has a preferential binding for N-acetyllactosamine residues on cell surface glycoconjugates. Galectin-3 interacts with several ligands both intracellularly and extracellularly and influences various pathways and processes via its CRD binding activity. It binds Bcl-2, CD95, Nucling, Alix/AIP1, synexin, and regulates apoptosis. Its interaction with activated K-Ras protein affects cell proliferation and survival. β-catenin is its binding partner in the Wnt signaling pathway. Galectin-3 binds to laminin, fibronectin, hensin, elastin, collagen IV, and tenascin-C and tenascin-R to modulate cell–ECM adhesion. In addition, it also binds α1β1, αvβ3, and αMβ1 integrins, the main proteins involved in cell adhesion (Table 2). A germ-line mutation at position 191 (rs4644) substituting amino acid proline64 to histidine makes this protein susceptible to MMP cleavage and enhances its migratory and angiogenic potential (15Nangia-Makker P. Raz T. Tait L. Hogan V. Fridman R. Raz A. Galectin-3 cleavage: a novel surrogate marker for matrix metalloproteinase activity in growing breast cancers.Cancer Res. 2007; 67: 11760-11768Crossref PubMed Scopus (74) Google Scholar, 16Balan V. Nangia-Makker P. Schwartz A.G. Jung Y.S. Tait L. Hogan V. et al.Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): a pilot study.Cancer Res. 2008; 68: 10045-10050Crossref PubMed Scopus (0) Google Scholar). It was reported that cleaved galectin-3 had stronger affinity for glycoconjugates than the full-length protein (17Ochieng J. Green B. Evans S. James O. Warfield P. Modulation of the biological functions of galectin-3 by matrix metalloproteinases.Biochim. Biophys. Acta. 1998; 1379: 97-106Crossref PubMed Scopus (124) Google Scholar), while some other interactions require both N-terminus domain and CRD motifs. Galectin-3 displays multivalency by the hydrophobic interactions of the N terminal with itself and with the CRD forming a fuzzy complex, which is the characteristic of intrinsically disordered proteins to achieve liquid–liquid phase separation (18Lin Y.H. Qiu D.C. Chang W.H. Yeh Y.Q. Jeng U.S. Liu F.T. et al.The intrinsically disordered N-terminal domain of galectin-3 dynamically mediates multisite self-association of the protein through fuzzy interactions.J. Biol. Chem. 2017; 292: 17845-17856Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar). Additional functional oligomeric states exist due to the dynamic homodimerization of the N terminal. It is generally accepted that galectin-3 oligomerization gives rise to changes in activity, which are associated with and reflected in its diverse biological functions. Galectin-3 oligomer forms a lattice with T cell surface receptors that prevents their uncontrolled activation (19Demetriou M. Granovsky M. Quaggin S. Dennis J.W. Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation.Nature. 2001; 409: 733-739Crossref PubMed Scopus (739) Google Scholar), and its cross-linking with either EGF and TGF-β receptors delays their internalization and degradation (20Pugliese G. Iacobini C. Pesce C.M. Menini S. Galectin-3: an emerging all-out player in metabolic disorders and their complications.Glycobiology. 2015; 25: 136-150Crossref PubMed Scopus (80) Google Scholar). Table 2 reflects the several biological processes regulated by C-terminal and N-terminal domains of galectin-3 in association with various binding partners.Table 2Binding partners of galectin-3 C-terminal and N-terminalC-terminalFunctionReferenceBcl2ApoptosisYang et al, 1996 (145Yang R.Y. Hsu D.K. Liu F.T. Expression of galectin-3 modulates T-cell growth and apoptosis.Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6737-6742Crossref PubMed Scopus (676) Google Scholar)CD95ApoptosisFukumori et al, 2004 (146Fukumori T. Takenaka Y. Oka N. Yoshii T. Hogan V. Inohara H. et al.Endogenous galectin-3 determines the routing of CD95 apoptotic signaling pathways.Cancer Res. 2004; 64: 3376-3379Crossref PubMed Scopus (109) Google Scholar)NuclingApoptosisLiu et al, 2004 (147Liu L. Sakai T. Sano N. Fukui K. Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kappaB signalling.Biochem. J. 2004; 380: 31-41Crossref PubMed Scopus (0) Google Scholar)Alix/AIP1ApoptosisLiu et al, 2002 (148Liu F.T. Patterson R.J. Wang J.L. Intracellular functions of galectins.Biochim. Biophys. Acta. 2002; 1572: 263-273Crossref PubMed Scopus (558) Google Scholar)K-RasCell proliferationEelad-sfadia et al, 2004 (149Elad-Sfadia G. Haklai R. Balan E. Kloog Y. Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity.J. Biol. Chem. 2004; 279: 34922-34930Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar)AktCell ProliferationLee et al, 2003 (150Lee Y.J. Song Y.K. Song J.J. Siervo-Sassi R.R. Kim H.R. Li L. et al.Reconstitution of galectin-3 alters glutathione content and potentiates TRAIL-induced cytotoxicity by dephosphorylation of Akt.Exp. Cell Res. 2003; 288: 21-34Crossref PubMed Scopus (0) Google Scholar), Oka et al, 2005 (151Oka N. Nakahara S. Takenaka Y. Fukumori T. Hogan V. Kanayama H.O. et al.Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells.Cancer Res. 2005; 65: 7546-7553Crossref PubMed Scopus (0) Google Scholar)β-cateninWnt signalingShimura et al, 2004 (152Shimura T. Takenaka Y. Tsutsumi S. Hogan V. Kikuchi A. Raz A. Galectin-3, a novel binding partner of beta-catenin.Cancer Res. 2004; 64: 6363-6367Crossref PubMed Scopus (183) Google Scholar)LamininECM adhesionMassa et al, 1993 (153Massa S.M. Cooper D.N. Leffler H. Barondes S.H. L-29, an endogenous lectin, binds to glycoconjugate ligands with positive cooperativity.Biochemistry. 1993; 32: 260-267Crossref PubMed Scopus (229) Google Scholar),FibronectinECM adhesionSato et al, 1992 (154Sato S. Hughes R.C. Binding specificity of a baby hamster kidney lectin for H type I and II chains, polylactosamine glycans, and appropriately glycosylated forms of laminin and fibronectin.J. Biol. Chem. 1992; 267: 6983-6990Abstract Full Text PDF PubMed Google Scholar)HensinECM adhesionHikita et al, 2000 (155Hikita C. Vijayakumar S. Takito J. Erdjument-Bromage H. Tempst P. Al-Awqati Q. Induction of terminal differentiation in epithelial cells requires polymerization of hensin by galectin 3.J. Cell Biol. 2000; 151: 1235-1246Crossref PubMed Scopus (0) Google Scholar)ElastinECM adhesionOchieng et al, 1998 (156Ochieng J. Warfield P. Green-Jarvis B. Fentie I. Galectin-3 regulates the adhesive interaction between breast carcinoma cells and elastin.J. Cell Biochem. 1999; 75: 505-514Crossref PubMed Scopus (82) Google Scholar)Collagen IVECM adhesionOchieng et al, 1998 (157Ochieng J. Leite-Browning M.L. Warfield P. Regulation of cellular adhesion to extracellular matrix proteins by galectin-3.Biochem. Biophys. Res. Commun. 1998; 246: 788-791Crossref PubMed Scopus (180) Google Scholar)Tenascin-C&-RECM adhesionProbstmeier et al, 1995 (158Probstmeier R. Montag D. Schachner M. Galectin-3, a beta-galactoside-binding animal lectin, binds to neural recognition molecules.J. Neurochem. 1995; 64: 2465-2472Crossref PubMed Google Scholar))α1β1 integrinCell adhesionOchieng et al, 1998 (157Ochieng J. Leite-Browning M.L. Warfield P. Regulation of cellular adhesion to extracellular matrix proteins by galectin-3.Biochem. Biophys. Res. Commun. 1998; 246: 788-791Crossref PubMed Scopus (180) Google Scholar)CD11b/CD18Inflammatory macrophageDong et al, 1997 (28Dong S. Hughes R.C. Macrophage surface glycoproteins binding to galectin-3 (Mac-2-antigen).Glycoconj J. 1997; 14: 267-274Crossref PubMed Scopus (130) Google Scholar)Lamp-1 and -2Inflammatory macrophageDong et al, 1997 (28Dong S. Hughes R.C. Macrophage surface glycoproteins binding to galectin-3 (Mac-2-antigen).Glycoconj J. 1997; 14: 267-274Crossref PubMed Scopus (130) Google Scholar)IgEInflammationCherayil et al, 1989 (159Cherayil B.J. Weiner S.J. Pillai S. The Mac-2 antigen is a galactose-specific lectin that binds IgE.J. Exp. Med. 1989; 170: 1959-1972Crossref PubMed Scopus (218) Google Scholar)CD44Cargo protein internalizationLakshminarayan et al, 2014 (160Lakshminarayan R. Wunder C. Becken U. Howes M.T. Benzing C. Arumugam S. et al.Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers.Nat. Cell Biol. 2014; 16: 595-606Crossref PubMed Scopus (190) Google Scholar)CD98Membrane traffickingDalton et al, 2007 (161Dalton P. Christian H.C. Redman C.W. Sargent I.L. Boyd C.A. Membrane trafficking of CD98 and its ligand galectin 3 in BeWo cells–implication for placental cell fusion.FEBS J. 2007; 274: 2715-2727Crossref PubMed Scopus (0) Google Scholar)CD66Inflammatory neutrophilsFeuk-Lagersted et al,1999 (162Feuk-Lagerstedt E. Movitz C. Pellme S. Dahlgren C. Karlsson A. Lipid raft proteome of the human neutrophil azurophil granule.Proteomics. 2007; 7: 194-205Crossref PubMed Scopus (35) Google Scholar)N-terminalFunctionReferenceEGFRCross-linking & endocytosisPartridge et al, 2004 (163Partridge E.A. Le Roy C. Di Guglielmo G.M. Pawling J. Cheung P. Granovsky M. et al.Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis.Science. 2004; 306: 120-124Crossref PubMed Scopus (591) Google Scholar); Liu 2012 (164Liu W. Hsu D.K. Chen H.Y. Yang R.Y. Carraway 3rd, K.L. Isseroff R.R. et al.Galectin-3 regulates intracellular trafficking of EGFR through Alix and promotes keratinocyte migration.J. Invest. Dermatol. 2012; 132: 2828-2837Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar)TGFβRCross linking& endocytosisPartridge et al, 2004 (163Partridge E.A. Le Roy C. Di Guglielmo G.M. Pawling J. Cheung P. Granovsky M. et al.Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis.Science. 2004; 306: 120-124Crossref PubMed Scopus (591) Google Scholar)CD147Clustering &MMP9 inductionMauris et al, 2014 (138Mauris J. Woodward A.M. Cao Z. Panjwani N. Argueso P. Molecular basis for MMP9 induction and disruption of epithelial cell-cell contacts by galectin-3.J. Cell Sci. 2014; 127: 3141-3148Crossref PubMed Scopus (71) Google Scholar)AlixHIV infectionWang et al, 2014 (139Wang S.F. Tsao C.H. Lin Y.T. Hsu D.K. Chiang M.L. Lo C.H. et al.Galectin-3 promotes HIV-1 budding via association with Alix and Gag p6.Glycobiology. 2014; 24: 1022-1035Crossref PubMed Scopus (19) Google Scholar)AlixT cell receptor (TCR) downregulationChen et al, 2009 (165Chen H.Y. Fermin A. Vardhana S. Weng I.C. Lo K.F. Chang E.Y. et al.Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse.Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 14496-14501Crossref PubMed Scopus (132) Google Scholar)Bacterial LPSInflammationLo et al, 2021 (142Lo T.H. Chen H.L. Yao C.I. Weng I.C. Li C.S. Huang C.C. et al.Galectin-3 promotes noncanonical inflammasome activation through intracellular binding to lipopolysaccharide glycans.Proc. Natl. Acad. Sci. U. S. A. 2021; 118e2026246118Crossref Scopus (6) Google Scholar)Abbreviations: Alix, ALG2 interacting protein X; CEA, carcinoembryonic antigen. Open table in a new tab Abbreviations: Alix, ALG2 interacting protein X; CEA, carcinoembryonic antigen. Galectin-3 is a profibrotic molecule and implicated in modulation of fibroblasts and macrophage activity in chronically inflamed lung, liver, kidney, heart, skin, blood vessels, etc. affecting common fibroproliferative pathways leading to fibrosis (21Hara A. Niwa M. Noguchi K. Kanayama T. Niwa A. Matsuo M. et al.Galectin-3 as a next-generation biomarker for detecting early stage of various diseases.Biomolecules. 2020; 10: 389Crossref PubMed Scopus (50) Google Scholar, 22Miah A. S P. Tongue P. Roach K. Bradding P. Gooptu B. Ex vivo studies of the gal-3-fibrosome hypothesis in IPF and non-fibrotic control lung tissue and myofibroblasts..Thorax. 2019; 74: A57Google Scholar). It is a proinflammatory molecule (23Liu F.T. Hsu D.K. The role of galectin-3 in promotion of the inflammatory response.Drug News Perspect. 2007; 20: 455-460Crossref PubMed Scopus (45) Google Scholar). It regulates immune functions and mediates acute and chronic inflammation. It activates and is abundantly expressed in cells of myeloid origin, such as monocytes, macrophages, dendritic cells, and neutrophils (24Fulton D.J.R. Li X. Bordan Z. Wang Y. Mahboubi K. Rudic R.D. et al.Galectin-3: a harbinger of reactive oxygen species, fibrosis, and inflammation in pulmonary arterial hypertension.Antioxid. Redox Signal. 2019; 31: 1053-1069Crossref PubMed Scopus (14) Google Scholar). It interacts with inflammatory cytokines TGF-β and CD98 expressed by migrating inflammatory cells and plays a major role in the profibrotic response (5Walton K.L. Johnson K.E. Harrison C.A. Targeting TGF-beta mediated SMAD signaling for the prevention of fibrosis.Front. Pharmacol. 2017; 8: 461Crossref PubMed Scopus (298) Google Scholar). In galectin-3–deficient mice, a dramatic reduction in fibrosis in response to TGF-β and bleomycin was observed accompanied with reduced epithelial to mesenchymal transition and myofibroblast activation (25MacKinnon A.C. Farnworth S.L. Hodkinson P.S. Henderson N.C. Atkinson K.M. Leffler H. et al.Regulation of alternative macrophage activation by galectin-3.J. Immunol. 2008; 180: 2650-2658Crossref PubMed Scopus (397) Google Scholar, 26Mackinnon A.C. Gibbons M.A. Farnworth S.L. Leffler H. Nilsson U.J. Delaine T. et al.Regulation of transforming growth factor-beta1-driven lung fibrosis by galectin-3.Am. J. Respir. Crit. Care Med. 2012; 185: 537-546Crossref PubMed Scopus (346) Google Scholar). Galectin-3 is instrumental in TGF-β1–induced fibroblasts differentiation via the MAPK/extracellular signal-regulated kinase (ERK)-ERK 1/2 signaling pathway (Fig. 1). It aids the extravasation of inflammatory cells and binds to specific cell surface receptors on macrophages (CD11b, CD98) and on neutrophils (CD66). It is upregulated in alternative macrophage activation by IL4 and IL13, and it activates PI3K via binding to CD98 and aids in increased collagen deposition (27Sato S. Ouellet N. Pelletier I. Simard M. Rancourt A. Bergeron M.G. Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia.J. Immunol. 2002; 168: 1813-1822Crossref PubMed Google Scholar, 28Dong S. Hughes R.C. Macrophage surface glycoproteins binding to galectin-3 (Mac-2-antigen).Glycoconj J. 1997; 14: 267-274Crossref PubMed Scopus (130) Google Scholar) by differentiation of resting fibroblasts into myofibroblasts leading to scar formation (29Slack R.J. Mills R. Mackinnon A.C. The therapeutic potential of galectin-3 inhibition in fibrotic disease.Int. J. Biochem. Cell Biol. 2021; 130: 105881Crossref PubMed Scopus (18) Google Scholar) (Fig. 1). Hepatitis B and Hepatitis C virus infections, innate immunity, and chronic inflammation play a role in the pathogenesis of liver metabolic disorders, nonalcoholic fatty liver disease, liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Chronic liver disease and cirrhosis result in ∼35,000 deaths each year in the US and for approximately two million deaths per year worldwide. The major histological components of the liver consist of (i) hepatocytes, constituting the parenchyma, (ii) stroma, (iii) sinusoids (the capillaries travelling between hepatocytes), and (iv) the spaces of Disse, which are located between the hepatocytes and the sinusoids. The liver sinusoids are a unique structure and are classified as discontinuous capillaries as they do not have a continuous endothelial lining but are endowed with fenestrated endothelium, which enables liver functions like ultrafiltration, endocytosis, and immunological activities. The spaces of Disse is enriched in collagen IV and perlecan but lacks laminin and nidogen (other components of the basement membrane). Sinusoidal capillarization is characterized by the formation of the basal lamina, loss of fenestrae, and transformation of the sinusoids into the continuous capillary. This interferes with hepatic microcirculation and leads to hepatic dysfunction (30Martine