Lung homeostasis is maintained by the interactions between CX3CR1-expressing interstitial macrophage and lung commensal bacteria.

Abstract As an anti-inflammatory cytokine, IL10 plays an important role in modulating immune responses. However, it remains relatively unknown about the importance of IL10-IL10 receptor (IL10R) signaling in maintaining lung homeostasis. Here we investigated that IL10R signaling of lung interstitial macrophages (IMs) contributes to the maintenance of tissue homeostasis by preventing fibrosing lung inflammation. We observed that IL10-deficient mice spontaneously induced lung inflammation in adulthood. In parallel, IL10R-deficiency of IMs identically induced the inflammatory phenotypes observed in IL10-deficient mice. Antibiotics treatments, 16S rRNA-Sequencing analysis, and germ-free (GF) animals allowed us to determine that the lung inflammation occurring in the absence of IL10 or IL10R was triggered by lung commensal dysbiosis. Furthermore, we identified that two distinct commensal microbes (D. Acidovorans and R. Erythropolis) dominantly colonized in the lung of mice lacking IL10R in IMs, where these commensals initiate lung inflammation. Collectively, our data highlight that IL10R signaling of IMs contributes to lung homeostasis by restricting commensal dysbiosis and prevents progressive lung fibrosis.