Reciprocal inflammatory signals establish profibrotic cross-feeding metabolism

Abstract

SummaryWhen monocyte-derived macrophages are recruited to injured tissues, they can induce a maladaptive fibrotic response characterized by excessive production of fibrillar collagen from local fibroblasts. Macrophages initiate the fibrotic programming of fibroblasts via paracrine factors, but it is unclear if reciprocal responses from the fibroblasts trigger pro-fibrotic programming of macrophages to establish a collaborative feed-forward fibrotic circuit. We identify macrophage-fibroblast cross talk necessary for injury-associated fibrosis, in which macrophages induce interleukin 6 (IL-6) expression in fibroblasts via purinergic receptor P2rx4 signaling and IL-6 induces arginase 1 (Arg1) expression in macrophages. Surprisingly,Arg1contributes to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts use as a substrate to synthesize proline, a uniquely abundant constituent of fibrillar collagen. Taken together, we define a bidirectional circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.