Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation

Abstract

Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.

Novel mechanisms and functions of complement

“…A recent study has dissected how the FH variant (H402Y) might promote inflammatory damage in AMD. FH binding to CR3 was shown to restrain thrombospondin-1 (TSP-1) activation of the integrin-associated CD47 receptor, which is required for homeostatic elimination of subretinal phagocytes (Fig.3c) 80 . Notably, the AMD-associated FH variant H402Y potentiates this inhibitory effect resulting in pathologic subretinal accumulation of phagocytes.…”

Compliments of Factor H: What’s in it for AMD?

“…Complement-inhibiting drugs are being developed and tested on the premise that complement activation underlies AMD pathology. Calippe et al (2017) now provide new insight into the role of CFH in AMD that is as surprising as it is compelling, revealing that the role of CFH in AMD is non-canonical and separate from the complement pathway.…”

“…In this issue of Immunity , Calippe et al (2017) uncover a non-canonical role for CFH in the inhibition of mononuclear phagocyte elimination from sub-retinal lesions, providing insight into the pathophysiology of AMD associated with CFH variants. …”

“…Using two different mouse models of AMD ( Cx3cr1 −/− mice and TRE2 humanized transgenic mice) Calippe et al (2017) dispel this notion, demonstrating a different role for CFH in AMD pathogenesis. First, they show that genetic deficiency of Cfh diminishes rather than aggravates AMD parameters, in contrast to what would be expected if its action were via complement inhibition.…”

Nicotinamide as a treatment option of Age-Related Macular Degeneration

“…Given the strong involvement of complement in AMD (genetic association [7], complement proteins in drusen [4,8,9], ARMS2 protein function in complement [10], fctor H on microglial [11] and the dramatic reduction of C3 expression levels in iPSC-RPE lines upon NAM treatment, justi ied the question by the investigators whether the NAM effect was largely explained by the reduction of C3 transcription. To answer this question, the authors inhibited C3 expression in their iPSC cell models via shRNA.…”