| dc.description.abstract | Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the U.S. Pentraxins are a group of evolutionarily conserved proteins that have profound effects of the innate immune system and regulate the development of fibrosis. The pentraxin Serum Amyloid P (SAP) alleviates fibrosis in mice and two human clinical trials, whereas C-reactive protein (CRP) which resembles SAP exacerbates fibrosis. Surprisingly, these two pentraxins bind the same Fcγ receptors (FcγR) with similar affinities but have opposite effects. In this dissertation, I elucidate the role of FcγR in the regulation of the innate immune system by pentraxins. I find that although FcγR play a role in the regulation of immune cells by SAP, they are not necessary for SAP effects. SAP mainly uses the C-type lectin receptor DC-SIGN to alter immune responses and through its interaction with DC-SIGN SAP differentiates itself from CRP. I also found that a polycyclic aminothiazole DC-SIGN ligand and anti-DC-SIGN antibodies mimic the effects of SAP in vitro. In mice, the aminothiazole alleviates acute lung inflammation and pulmonary fibrosis. The aminothiazole alleviates pulmonary fibrosis by upregulating the anti-inflammatory cytokine IL-10 in lung epithelial cells. Together, these results suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that the aminothiazole and anti-DC-SIGN antibodies are potential therapeutics for fibrosis. | en |
