title: DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice.
abstract: Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the United States. Two closely related human serum proteins, serum amyloid P (SAP) and C-reactive protein (CRP), strongly affect fibrosis. In multiple animal models, and in Phase 1 and Phase 2 clinical trials, SAP affects several aspects of the innate immune system to reduce fibrosis, whereas CRP appears to potentiate fibrosis. However, SAP and CRP bind the same Fcγ receptors (FcγR) with similar affinities, and why SAP and CRP have opposing effects is unknown. Here, we report that SAP but not CRP binds the receptor DC-SIGN (SIGN-R1) to affect the innate immune system, and that FcγR are not necessary for SAP function. A polycyclic aminothiazole DC-SIGN ligand and anti-DC-SIGN antibodies mimic SAP effects in vitro. In mice, the aminothiazole reduces neutrophil accumulation in a model of acute lung inflammation and, at 0.001 mg/kg, alleviates pulmonary fibrosis by increasing levels of the immunosuppressant IL-10. DC-SIGN (SIGN-R1) is present on mouse lung epithelial cells, and SAP and the aminothiazole potentiate IL-10 production from these cells. Our data suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that DC-SIGN is a target for antifibrotics.
authors.affiliation: Department of Biology, MS-3474, Texas A&M University, College Station, TX 77843-3474.
authors.forename: Nehemiah
authors.initials: N
authors.lastname: Cox
authors.affiliation: Department of Biology, MS-3474, Texas A&M University, College Station, TX 77843-3474.
authors.forename: Darrell
authors.initials: D
authors.lastname: Pilling
authors.affiliation: Department of Biology, MS-3474, Texas A&M University, College Station, TX 77843-3474 rgomer@tamu.edu.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Gomer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000276:immunology* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D002097:C-Reactive Protein; D015815:Cell Adhesion Molecules; D016753:Interleukin-10; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D000683:Serum Amyloid P-Component; D013844:Thiazoles; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C004483:2-aminothiazole
keywords: DC-SIGN; IL-10; fibrosis; pentraxin; serum amyloid P