Neutrophil-driven CD206hiMHCIIlo macrophages are critical for skin fibrosis during systemic sclerosis

Abstract Systemic sclerosis (SSc) is a recalcitrant autoimmune disease characterized by progressive fibrosis in the skin and internal organs, such as the lungs. A key feature of this disease is the infiltration of innate immune cells, yet, how they contribute to the pathogenesis of SSc is largely unknown. Here, we demonstrated that the CD206 hi MHCII lo macrophages were the dominant immune cell population accumulated in the fibrotic skin of SSc mice, and these cells were found to be critical in mediating the profibrotic response by producing TGF-β1 in a MerTK signaling-dependent manner. Interestingly, the neutrophil infiltration was a prerequisite for the accumulation of CD206 hi MHCII lo macrophages and depletion of neutrophils or inhibition of CXCR1/2 could reduce CD206 hi MHCII lo macrophages and alleviate SSc progression. Detailed investigations revealed that in the fibrotic skin, neutrophils released neutrophil extracellular traps (NETs) ensnared macrophages and were responsible for the differentiation of CD206 hi MHCII lo macrophages. Our findings uncovered a key role of the neutrophil-macrophage-fibrosis axis in the pathogenesis of SSc and provide critical information for the development of novel therapeutic strategies.