Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis

TLDR

Circulating CD45+ collagen‑I+ CXCR4+ fibrocytes have been identified, yet their role in fibrosis remains unproven and pulmonary fibrosis was traditionally attributed solely to resident lung fibroblasts. This study aims to determine whether human CD45+ collagen‑I+ CXCR4+ fibrocytes migrate toward CXCL12 and accumulate in the lungs during bleomycin‑induced pulmonary fibrosis. Using a murine bleomycin model, the authors tracked CD45+ collagen‑I+ CXCR4+ fibrocytes, quantified their lung recruitment, and assessed the effect of anti‑CXCL12 antibodies on this process and collagen deposition. They found that fibrocyte recruitment peaked with increased lung collagen, and neutralizing CXCL12 reduced recruitment and fibrosis, providing the first evidence that circulating fibrocytes drive pulmonary fibrosis.

Abstract

Previous reports have identified a circulating pool of CD45+ collagen I+ CXCR4+ (CD45+Col I+CXCR4+) cells, termed fibrocytes, that traffic to areas of fibrosis. No studies have demonstrated that these cells actually contribute to fibrosis, however. Pulmonary fibrosis was originally thought to be mediated solely by resident lung fibroblasts. Here we show that a population of human CD45+Col I+CXCR4+ circulating fibrocytes migrates in response to CXCL12 and traffics to the lungs in a murine model of bleomycin-induced pulmonary fibrosis. Next, we demonstrated that murine CD45+Col I+CXCR4+ fibrocytes also traffic to the lungs in response to a bleomycin challenge. Maximal intrapulmonary recruitment of CD45+Col I+CXCR4+ fibrocytes directly correlated with increased collagen deposition in the lungs. Treatment of bleomycin-exposed animals with specific neutralizing anti-CXCL12 Ab’s inhibited intrapulmonary recruitment of CD45+Col I+CXCR4+ circulating fibrocytes and attenuated lung fibrosis. Thus, our results demonstrate, we believe for the first time, that circulating fibrocytes contribute to the pathogenesis of pulmonary fibrosis.