Abstract

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 transcription factor JUN and increased promoter accessibilities of both JUN and 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 IL-6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study demonstrates the efficiency of combining different immunotherapies in treating scleroderma and provides a rationale for combining CD47 and IL-6 inhibition in clinical trials.

Highlights

  • Scleroderma is the fibrotic skin manifestation of the autoimmune diseases morphea and systemic sclerosis, causing significant morbidity

  • We ran these studies after JUN knockout and under vismodegib to study the effects of JUN and hedgehog inhibition in scleroderma fibroblasts (Figure 2A)

  • After 2 days, p-JUN was significantly increased on the hydrogel, a result that we confirmed with primary pulmonary fibroblasts (Figure 2E)

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Summary

Introduction

Scleroderma is the fibrotic skin manifestation of the autoimmune diseases morphea and systemic sclerosis, causing significant morbidity. Current treatments rely on immune suppression and primarily aim at stopping or slowing down the progression of scleroderma [1, 2]. These treatments only bring temporary relief to most patients. Considering that scleroderma leads to the accumulation of diseased fibroblasts, we hypothesized that the inhibition of the “don’t-eat-me-signal” CD47 would help the body’s immune system remove abnormal fibroblasts. This therapeutic approach would stop the disease as immune suppression does and could permit its remission, thereby offering a breakthrough for the treatment of scleroderma

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