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.
journal_name
Proc Natl Acad Sci U S Aauthors
Cox N,Pilling D,Gomer RHdoi
10.1073/pnas.1500956112subject
Has Abstractpub_date
2015-07-07 00:00:00pages
8385-90issue
27eissn
0027-8424issn
1091-6490pii
1500956112journal_volume
112pub_type
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1973-10-01 00:00:00
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更新日期:1992-05-15 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1993-03-01 00:00:00