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vsig4

Properties1
aliasesCRIg, Z39Ig, Z39IG, complement receptor of the immunoglobulin superfamily, VSIG4

16 min read

VSIG4 (V-set and immunoglobulin domain-containing protein 4; CRIg)

VSIG4 (also CRIg — Complement Receptor of the Immunoglobulin superfamily — and Z39Ig) is a type I single-pass transmembrane glycoprotein with two Ig-like extracellular domains, expressed selectively on resting tissue-resident macrophages — most prominently hepatic Kupffer cells, peritoneal and adipose tissue macrophages, and resident intestinal macrophages. It performs two distinct molecular functions: a complement receptor that binds C3b/iC3b fragments and mediates phagocytic clearance of complement-opsonized pathogens, and a B7-family-related co-inhibitory ligand that suppresses T-cell proliferation and IL-2 production. VSIG4 is a defining marker of the resting, anti-inflammatory/homeostatic macrophage state; expression is lost upon macrophage activation. In aging biology, VSIG4 has emerged as one of the conserved cross-species transcriptomic hallmarks of ageing, named alongside GPNMB, CDKN1A/p21, and EDA2R in the Tyshkovskiy et al. 2026 universal ageing signature — though its up-regulation with age carries an important interpretive nuance.

Identity

FieldValue
UniProtQ9Y279 (VSIG4_HUMAN) — Swiss-Prot (manually curated)
NCBI Gene11326
HGNCHGNC:17032
EnsemblENSG00000155659
Chromosomal locationXq12 (X-linked)
Mouse orthologVsig4 (mouse NCBI Gene ID 278180; chromosome X; one-to-one)
GenAgeNot in GenAge human as of 2026-05-29 needs-genage-check

Molecular biology

VSIG4 is encoded on chromosome Xq12 and belongs to the B7 superfamily of immune regulatory proteins — structurally related (two extracellular Ig-like domains), though phylogenetically distinct from classical B7 ligands (B7-1/CD80, B7-2/CD86, PD-L1/B7-H1).1 The canonical protein is 399 amino acids (confirmed via UniProt Q9Y279 sequence length); the protein carries:

  • Signal peptide — cleaved co-translationally
  • Extracellular domain — two Ig-like domains (Ig-like 1: residues 21–131; Ig-like 2: residues 143–226)
  • Single transmembrane helix
  • Short cytoplasmic tail

The extracellular domain binds the complement fragments C3b and iC3b directly and independently of divalent cations — distinguishing VSIG4 from CR3 (which requires Mg²⁺).2 It also binds the macroglobulin-like domains MG4/MG5 of C3b, a binding interface characterized by nanobody structural studies.3 Multiple splice isoforms are documented (five RefSeq transcripts: NM_007268.3, NM_001100431.2, NM_001184830.2, NM_001184831.2, NM_001257403.2).

A soluble VSIG4 ectodomain (sVSIG4) is generated by shedding from the macrophage surface and can be detected in plasma/serum; elevated sVSIG4 has been reported in macrophage-activation diseases and as a candidate biomarker of macrophage burden.4

Cell-type expression and complement receptor function

VSIG4 expression is among the most macrophage-selective of any immune gene. Seminal characterization by Helmy et al. 2006 identified CRIg as the principal complement receptor on hepatic Kupffer cells, responsible for rapid phagocytic capture of complement-opsonized pathogens from portal blood — explaining why CRIg-deficient mice show impaired bacterial clearance and increased infection susceptibility.5 Vogt et al. 2006 demonstrated that surface expression is strictly restricted to resting tissue macrophages and is absent upon macrophage activation by LPS or in autoimmune inflammatory foci — a key tissue-homeostasis restraint.1

Tissue-resident macrophage populations confirmed to express VSIG4 include:

  • Kupffer cells (liver) — highest expression; primary hepatic pathogen-clearance role
  • Adipose tissue macrophages — VSIG4⁺ fraction rises substantially with age (see § Aging context below)
  • Peritoneal macrophages — characterized by Gorgani et al. 2008 for complement-mediated phagocytosis2
  • Intestinal macrophages — CRIg expression on large-intestine macrophages mediates C3b-dependent phagocytosis6
  • Monocyte-derived dendritic cells — dexamethasone-inducible CRIg on human DCs correlates with suppressed T-cell responses7
  • Blood monocytes — CRIg facilitates adhesion and antimicrobial killing of Staphylococcus aureus8

The complement-binding function is further demonstrated by the CRIg/platelet-clearance axis: CRIg is the critical macrophage receptor for complement-dependent elimination of DAF/Crry-deficient platelets from circulation, while erythrocyte clearance uses a distinct pathway.9

DimensionStatus
Pathway conserved in humans?yes — complement-receptor and T-cell-inhibitory functions conserved; human DC CRIg expression demonstrated
Phenotype conserved in humans?partial — Kupffer-cell/liver pathogen-clearance conserved; age-related adipose tissue rise confirmed in mouse; limited direct human aging data
Replicated in humans?partial — aging transcriptomic signature replicated across species (Tyshkovskiy 2026); serum VSIG4 as aging biomarker has limited human cohort data

T-cell co-inhibitory function (B7-family axis)

VSIG4 functions as a negative regulator of T-cell activation through an as-yet incompletely characterized receptor–ligand interaction. Vogt et al. 2006 demonstrated that soluble VSIG4-Ig fusion molecules potently suppress both murine and human T-cell proliferation and IL-2 production in vitro, and reduce Th-cell-dependent IgG responses in vivo — establishing it as a co-inhibitory ligand mechanistically analogous to CTLA-4/B7-1 or PD-1/PD-L1, though using a macrophage (rather than antigen-presenting cell) as the presenting cell.1

Downstream anti-inflammatory signaling. VSIG4 ligation activates downstream pathways including PI3K/AKT (pro-survival/M2-polarizing) and inhibits TLR4/NF-κB (pro-inflammatory), promoting macrophage M2 polarization.10 Independently, VSIG4 suppresses NLRP3 inflammasome activation and pyroptosis — downregulated VSIG4 in inflammatory bowel disease tissue correlates with increased macrophage NLRP3 activity and epithelial damage.11 VSIG4 also attenuates NLRP3 after intracerebral hemorrhage via a JAK2–STAT3–A20 axis.12

This suppressive biology is well-adapted to tissue homeostasis in healthy conditions — resting Kupffer cells and adipose macrophages that express VSIG4 dampen local T-cell responses and prevent sterile inflammation in lipid-rich or pathogen-exposed environments. The loss of VSIG4 (whether by macrophage activation, replacement of resident macrophages with recruited monocytes, or reduced expression in disease) is therefore consistently pro-inflammatory in experimental models.

Why VSIG4 matters for aging: the Tyshkovskiy 2026 signature

The Tyshkovskiy et al. 2026 Nature paper (doi:10.1038/s41586-026-10542-3) — a meta-analysis of 11,165 transcriptomes across mouse, rat, macaque, and human — identified Vsig4 as one of a short list of conserved genes consistently up-regulated with ageing across rodents and primates. The paper explicitly names “Gpnmb, Vsig4, Cdkn1a and Eda2r” as headline conserved up-regulated genes in the cross-species ageing signature.13

Interpretive nuance — this rise is not straightforwardly pro-inflammaging. Unlike GPNMB (which is both a macrophage marker and a direct senescence/mortality biomarker with UK Biobank protein-level validation), the age-associated rise in VSIG4 most plausibly reflects:

  1. Expansion or accumulation of tissue-resident macrophage populations in aging tissues — consistent with the well-established accumulation of adipose tissue macrophages and hepatic Kupffer-cell alterations with age.
  2. Shifts in macrophage state composition — the ratio of VSIG4⁺ (resting, homeostatic) to VSIG4⁻ (activated, inflammatory) macrophages may increase not because total inflammation decreases but because the gross macrophage pool expands faster than activation states track it.
  3. A compensatory anti-inflammatory response — tissue VSIG4 induction as a restraining mechanism against rising inflammaging signals.

VSIG4 is itself immunosuppressive; its rise cannot be interpreted as a direct driver of chronic-inflammation in the way that, say, Cdkn1a up-regulation reflects increasing p21-mediated senescence. The tension between “VSIG4 is anti-inflammatory in every tested model” and “VSIG4 rises with age alongside pro-inflammatory markers” is an unresolved gap. no-mechanism

Aging-biomarker support: adipose tissue macrophages

Hall et al. 2020 provided the first systematic aging-context characterization: VSIG4⁺ adipose tissue macrophages (gWAT) increased 3.9-fold from 13% to 52% of the macrophage compartment between young (19-week) and aged (120-week) mice (p<0.001), with an additional 1.9-fold increase in per-cell VSIG4 expression intensity. In males, VSIG4 expression strongly correlated with both chronological age (r=0.82, p<0.001) and the physiological frailty index (r=0.82, p=0.002). In females, the age correlation was also significant (r=0.80, p=0.002) but the PFI correlation was not (r=0.42, p=0.17 — sex-specific difference in frailty-linked biology).14 This positions VSIG4 as a flow-cytometry-accessible aging biomarker at the cellular level in adipose tissue, though the frailty correlation is associational and the directionality (is rising VSIG4⁺ burden harmful, neutral, or compensatory?) remains open. no-mechanism

Emerging evidence ties VSIG4⁺ macrophage function to multiple age-associated diseases:

Liver (NAFLD/NASH/ALD). In metabolic liver disease, VSIG4⁺ resident Kupffer cells are reduced and protective: Vsig4-knockout mice show accelerated NAFLD steatosis and fibrosis, with NF-κB/TGF-β1 pathway up-regulation; bone marrow transplant from wild-type mice restores protection.15 VSIG4⁺ resident single-Kupffer cells improve hepatic inflammation and fibrosis in NASH compared to VSIG4⁻ populations.16 In alcoholic liver disease (ALD), CRIg⁻/⁻ mice show more severe ethanol-induced steatohepatitis, and soluble CRIg-Ig administration protects against ALD — establishing a therapeutic angle.17 The pattern is consistent: loss of VSIG4⁺ Kupffer cell identity → impaired bacterial clearance + pro-inflammatory shift → liver injury amplification.

Metabolic aging, hypertension, and diabetes. Liu et al. 2022 proposed that Vsig4/CRIg and gut microbial DNA are “key antagonistic players in healthy aging and age-associated development of hypertension and diabetes,” with hepatic VSIG4 expression protecting against bacterial DNA accumulation in tissues and downstream metabolic dysfunction.18

Renal aging. Li et al. 2014 showed VSIG4-expressing macrophages in kidney suppress T-cell infiltration and inflammation after obstructive injury (VSIG4 KO mice develop worse tubulointerstitial injury).19 Han et al. 2026 found VSIG4 expression increases with renal aging and is further accelerated in type 2 diabetic mice, with urinary VSIG4 correlating with albumin levels — positioning VSIG4 as a biomarker of renal aging pathology.20

Cardiac aging / gut-leak axis. Gao et al. 2023 demonstrated that gut-lumen-leaked bacterial DNA triggers myocardial inflammation and impairs cardiac contractility in aged mice via cGAS/STING; VSIG4⁺ macrophages block microbial extracellular vesicle spread, and restoring their population improves cardiac function.21 This links VSIG4 to the dysbiosis / gut-barrier / chronic-inflammation → cardiac aging axis.

Alzheimer’s disease / neuroinflammation. Yang et al. 2025 found serum VSIG4 significantly elevated in Alzheimer’s disease patients and correlated with neuroinflammatory markers (NfL, YKL-40, TNF-α) and cognitive performance decline — proposing VSIG4 as a predictor of both AD and advanced aging.22

Druggability (aging-context tier 3)

VSIG4 reaches druggability tier 3 on the aging-context convention (predicted druggable; high-quality probe demonstrated in rodents; no aging-validated clinical drug or human trial exists):

  • Soluble CRIg-Ig fusion protein was effective in rodent models of ALD (Duan 2021) and in suppressing T-cell responses in vivo (Vogt 2006). These establish target engagement and functional proof-of-concept at the molecular level, but no clinical development program for aging has been announced.
  • Anti-VSIG4 nanobody (Nb119) binds both mouse and human VSIG4 with structural characterization.3 Functional use in macrophage depletion or complement-blockade studies has been explored but not advanced clinically.
  • VSIG4-targeting in tumor immunology — the lung cancer model (Liao 2014) and ovarian cancer data (Byun 2017) have motivated interest in anti-tumor antibodies that block macrophage VSIG4-mediated immunosuppression. These are early-stage and oncology-focused.

No active ClinicalTrials.gov entries for VSIG4 as an aging or senolytic target were found as of 2026-05-29. clinical-trials-active: 0 needs-clinical-trials-recheck

Therapeutic opportunity. The most direct aging-context strategy would be to restore VSIG4⁺ resident macrophage identity in tissues where homeostatic Kupffer cells and adipose macrophages are replaced by recruited pro-inflammatory monocytes with aging — analogous to targeting tissue-macrophage niche signals to maintain anti-inflammatory macrophage populations. This hypothesis-level strategy has no validated agent.

Gaps

  • Whether VSIG4 up-regulation with age causes, compensates for, or is merely correlated with chronic inflammation is unresolved — every tissue model shows VSIG4 is anti-inflammatory; the rise is more likely a marker of macrophage expansion or compensatory restraint than a driver of inflammaging. no-mechanism
  • gtex-aging-correlation (age-stratified Spearman ρ) not yet queried from GTEx v10 age-stratified endpoint. needs-gtex-age-stratified
  • VSIG4 is not in GenAge as of 2026-05-29. needs-genage-check
  • Chromosomal location Xq12: X-linkage means sex-stratified expression analyses are critical; most aging mouse studies do not consistently report sex stratification of VSIG4⁺ macrophage frequency. needs-sex-stratified-data
  • No Mendelian randomization study for VSIG4 and aging or mortality outcomes. X-linked genes present additional instrument-selection challenges for MR. mr-not-attempted
  • The identity of the T-cell counter-receptor(s) for VSIG4’s co-inhibitory function is not established (distinct from the complement-binding receptor C3b/iC3b). no-mechanism
  • UK Biobank plasma VSIG4 proteomic data (if present in Olink panels) has not been systematically reported for aging/mortality — in contrast to GPNMB which is explicitly validated in Tyshkovskiy 2026. needs-human-replication

Footnotes

Footnotes

  1. doi:10.1172/JCI25673 · Vogt L et al. · J Clin Invest 2006 · in-vitro + in-vivo (mouse and human T cells; BALB/c and C57BL/6 mice) · VSIG4 identified as B7 family–related co-inhibitory ligand via HMM screen; surface expression restricted to resting peritoneal macrophages (CD11b⁺/GR1⁻/F480⁺) and tissue-resident macrophages (liver Kupffer cells, adipose tissue, heart, thymus medulla); absent on activated macrophages (LPS/thioglycolate), DCs, neutrophils, T cells, B cells; absent in intestines, kidney, skeletal muscle, lymph node, lung, brain; soluble VSIG4-Ig (5 µg/ml) inhibits murine and human CD4⁺ and CD8⁺ T-cell proliferation and IL-2 production in vitro (p<0.05); in vivo i.p. VSIG4-Ig treatment (500 µg) reduced p33-specific CD8⁺ T cells ~2.3-fold (p=0.038) and IFN-γ⁺ CD8⁺ T cells ~3.5-fold; reduced Th-dependent IgG ~2-fold (p=0.001); Th-independent IgM marginally affected; human Z39Ig (extracellular domain aa 1–280) also inhibits murine and human T-cell proliferation. PDF verified 2026-05-29 (full text read). ↩ ↩2 ↩3

  2. doi:10.4049/jimmunol.181.11.7902 · Gorgani NN et al. · J Immunol 2008 · in-vitro (peritoneal macrophage) · CRIg⁺ macrophages show enhanced complement-opsonized phagocytosis; C3b binding independent of divalent cations (distinct from CR3). archive not_oa; PDF not available locally. ↩ ↩2

  3. doi:10.1016/j.imbio.2016.11.008 · Wen Z et al. · Immunobiology 2017 · structural biology · Nb119 nanobody binds VSIG4 at the C3b MG4/MG5 interface; cross-reactive mouse and human. Background claim — archive not checked. ↩ ↩2

  4. doi:10.1016/j.canlet.2022.215996 · Liu X et al. · Cancer Letters 2023 · review · VSIG4 biology overview; complement and T-cell suppression; soluble VSIG4 as biomarker; implications for inflammation and cancer. archive not_oa; PDF not available locally. ↩

  5. doi:10.1016/j.cell.2005.12.039 · Helmy KY et al. · Cell 2006 · in-vivo (mouse, CRIg-deficient homologous-recombination KO) · CRIg (VSIG4/Z39Ig) identified as novel complement receptor on Kupffer cells and a subset of tissue-resident macrophages; binds C3b and iC3b (not C4b, C5–C9, native C3, C1, C2, C3a, C4); CRIg⁻/⁻ KO mice show ~60% reduction in E-IgM rosetting on Kupffer cells vs wild-type; impaired hepatic clearance of C3-opsonized circulating pathogens; CRIg localizes to constitutively recycling endosomes; human CRIg present in Kupffer cells, alveolar macrophages, synovial macrophages, adrenal gland macrophages, lamina propria histiocytes. PDF verified 2026-05-29 (pages 1–6 read). ↩

  6. doi:10.1177/1753425911400641 · Tanaka M et al. · Innate Immun 2012 · in-vitro/in-vivo (intestinal macrophage) · CRIg expression on large-intestine macrophages mediates C3b-dependent phagocytosis with distinct functional profile from peritoneal macrophages. Background claim — archive not checked. ↩

  7. doi:10.3389/fimmu.2019.02892 · Munawara U et al. · Front Immunol 2019 · in-vitro (human monocyte-derived DCs) · CRIg expressed on human DCs; dexamethasone-inducible; anti-CRIg antibodies overcome dexamethasone-induced T-cell suppression. DOI lookup confirmed (17 citations); PDF not downloaded (status: pending). ↩

  8. doi:10.1186/s12929-025-01212-z · Perveen K et al. · J Biomed Sci 2026 · in-vitro (human blood monocytes) · CRIg on monocytes facilitates adhesion and antimicrobial killing of S. aureus through complement-dependent mechanisms. Background claim — archive not checked. ↩

  9. doi:10.1182/blood-2008-01-134304 · Kim DD et al. · Blood 2008 · in-vivo (mouse, DAF/Crry-deficient platelets) · CRIg identified as critical receptor for complement-dependent platelet elimination; blockade rescues DAF/Crry⁻/⁻ platelets; distinct from erythrocyte clearance pathway. Background claim — archive pending. ↩

  10. doi:10.1556/2060.2022.00055 · Wang W et al. · Physiology International 2022 · in-vivo (rat, ischemia-reperfusion) · VSIG4 promotes cardiac macrophage M2 polarization via PI3K/AKT activation; inhibits TLR4/NF-κB; cardioprotective. Background claim — archive not checked. ↩

  11. doi:10.1016/j.tice.2023.102285 · Liao X et al. · Tissue Cell 2024 · in-vitro/in-vivo (mouse, IBD model) · VSIG4 overexpression suppresses NLRP3 inflammasome activation and pyroptosis in macrophages; downregulated in IBD tissue. DOI lookup confirmed; PDF not downloaded (status: pending). ↩

  12. doi:10.1007/s12640-021-00456-5 · Ji H et al. · Neurotoxicol Res 2022 · in-vivo (mouse, intracerebral hemorrhage) · VSIG4 overexpression reduces NLRP3 activation and improves neurological outcomes via JAK2–STAT3–A20 pathway. Background claim — archive not checked. ↩

  13. tyshkovskiy-2026-universal-transcriptomic-hallmarks · n=11,165 transcriptomes, 4 species · meta-analysis · elastic-net clock coefficients + mixed-effects gene-trait associations · model: mouse/rat/macaque/human, multi-tissue · Paper explicitly names “Gpnmb, Vsig4, Cdkn1a and Eda2r” as conserved upregulated genes across rodents and primates (main text, cross-species section). Note: the top clock-coefficient genes (also named in the clock results section) are Gpnmb, Cst7, and Cdkn1a; Vsig4 appears in the broader conserved upregulated gene list and the four-gene grouping. UK Biobank plasma protein mortality validation is provided for GPNMB, CDKN1A, and LGALS3 — not for VSIG4. Cross-checked against primary PDF pages 1–9 and verified study page 2026-05-29. ↩

  14. doi:10.1111/acel.13219 · Hall BM et al. · Aging Cell 2020 · in-vivo (mouse, longitudinal + cross-sectional, C57BL/6J and NIH Swiss strains) · VSIG4⁺ ATMs (CD11b⁺F4/80⁺) in gWAT increase 3.9-fold from 13% to 52% with age (p<0.001); Vsig4 protein increase confirmed by immunoblot ≥9-fold to 132 weeks; strong correlation with physiological frailty index (PFI) in males (r=0.82, p<0.001 for VSIG4 vs PFI; r=0.82, p=0.002 for VSIG4 vs age); in females, age correlation significant (r=0.80, p=0.002) but PFI correlation not significant (r=0.42, p=0.17); 1.9-fold increase in median fluorescence intensity of VSIG4 per ATM also observed with age. PDF verified 2026-05-29. ↩

  15. doi:10.1016/j.bbrc.2019.06.045 · Li S et al. · Biochem Biophys Res Commun 2019 · in-vivo (mouse, Vsig4-KO + bone marrow transplant) · VSIG4-KO mice develop accelerated NAFLD steatosis and fibrosis via NF-κB/TGF-β1; WT bone marrow transplant restores protection. archive not_oa; PDF not available locally. ↩

  16. doi:10.1007/s00011-023-01696-1 · Li J et al. · Inflamm Res 2023 · in-vitro/ex-vivo (mouse Kupffer cells) · VSIG4⁺ resident single-Kupffer cells produce less lipid accumulation, TNF-α, and α-SMA vs VSIG4⁻ population in NASH context. DOI lookup confirmed; PDF not downloaded (status: pending). ↩

  17. doi:10.1038/s41467-021-27385-3 · Duan M et al. · Nat Commun 2021 · in-vivo (mouse, CRIg⁻/⁻ + soluble CRIg-Ig treatment) · CRIg⁻/⁻ mice show worse ethanol-induced steatohepatitis and impaired bacterial clearance; soluble CRIg-Ig protects. DOI lookup confirmed (OA); PDF not downloaded (status: pending). ↩

  18. doi:10.3389/fendo.2022.1037465 · Liu W et al. · Front Endocrinol 2022 · in-vivo (mouse) · hepatic Vsig4 expression protects against bacterial DNA accumulation; proposed as key checkpoint for healthy aging vs age-associated hypertension and diabetes. DOI lookup confirmed; PDF not downloaded (status: pending). ↩

  19. doi:10.1007/s40620-013-0022-3 · Li XJ et al. · J Nephrology 2014 · in-vivo (mouse, VSIG4-KO, unilateral ureteral obstruction) · VSIG4-KO mice develop worse renal tubulointerstitial injury with greater T-cell infiltration and inflammatory markers. archive not_oa; PDF not available locally. ↩

  20. doi:10.3390/life16050732 · Han SY et al. · Life (Basel) 2026 · in-vivo (mouse; male db/db [type 2 diabetic] vs db/m controls followed 8–38 weeks) · intrarenal VSIG4 expression increased with age in db/m controls; appeared earlier and more predominantly in db/db diabetic mice; VSIG4 localized to distal tubular segments; urinary VSIG4 correlated strongly with urinary albumin levels (r=0.867, p<0.001); urinary albumin in db/db mice significantly higher from 8 weeks onward vs db/m, peaking at 38 weeks; klotho expression declined progressively. Authors conclude VSIG4 reflects aging-related kidney changes rather than diabetic injury alone. DOI confirmed via Crossref 2026-05-29; abstract-level verification only — PDF not downloaded. ↩

  21. doi:10.3389/fimmu.2023.1216344 · Gao H et al. · Front Immunol 2023 · in-vivo (aged mouse) · gut-leaked bacterial DNA triggers myocardial inflammation via cGAS/STING in aging; VSIG4⁺ macrophages block microbial EV spread; restoring VSIG4⁺ population improves cardiac function. DOI lookup confirmed; PDF not downloaded (status: pending). ↩

  22. doi:10.1177/13872877251329463 · Yang J et al. · J Alzheimers Dis 2025 · cross-sectional (human) · serum VSIG4 elevated in Alzheimer’s disease; correlated with NfL, YKL-40, TNF-α, and cognitive decline; proposed as predictor of AD and advanced aging. DOI lookup confirmed; PDF not downloaded (status: pending). ↩

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