RT Journal Article
SR Electronic
T1 CD47 prevents the elimination of diseased fibroblasts in scleroderma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.06.138222
DO 10.1101/2020.06.06.138222
A1 Tristan Lerbs
A1 Lu Cui
A1 Megan E. King
A1 Tim Chai
A1 Claire Muscat
A1 Tyler Shibata
A1 Gerlinde Wernig
YR 2020
UL http://biorxiv.org/content/early/2020/06/07/2020.06.06.138222.abstract
AB Scleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression, but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the “don’t-eat-me-signal” CD47 and whether blocking CD47 enables the body’s immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated JUN and increased promotor accessibilities of both JUN and the CD47. Next, we established our scleroderma model demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1-fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study is the first to demonstrate the efficiency of combining different immunotherapies in treating scleroderma and provide a rationale for combining CD47 and IL6 inhibition in clinical trials.Competing Interest StatementThe authors have declared no competing interest.