IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice

TLDR

Acute lung injury leading to inflammation and fibrosis, such as that induced by bleomycin, has poorly defined molecular mechanisms, including neutrophil and lymphocyte chemotactic factor expression, chronic inflammation, remodeling, and fibrosis. The study investigates the roles of IL‑1R1 and MyD88 in acute pulmonary injury. The authors employ a murine bleomycin‑induced pulmonary injury model to examine these signaling pathways. IL‑1R1 and MyD88 deficiency attenuates bleomycin‑induced lung inflammation, remodeling, and fibrosis; MyD88 signaling from radioresistant resident cells is essential; exogenous IL‑1β reproduces bleomycin pathology, while IL‑1R1 blockade reduces it; and inflammasome adaptor ASC is required for IL‑1β production and inflammation, establishing IL‑1R1/MyD88 signaling and the inflammasome as critical drivers and therapeutic targets of chronic lung inflammation and fibrosis.

Abstract

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1– and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1β recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1β production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.