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

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.

Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1β in idiopathic pulmonary fibrosis

“…Mice lacking the IL-1R1 receptor showed significantly reduced cellular infiltrates, alveolar wall destruction and collagen deposition. Moreover, blockade of the IL-1R1 receptor by exogenous IL-Ra (anakinra) dramatically reduced neutrophil influx and the formation of bleomycin-induced fibrosis in mice [8]. Altogether, IL-1 seems to be a critical cytokine and may possibly be a therapeutic target in IPF.…”

“…Mice with bleomycin-induced fibrosis have an up-regulated expression of IL-1b mRNA after instillation of bleomycin [20], and addition of recombinant IL-1b induces fibrotic remodelling [8]. Overexpression of IL-1b in rat lungs after intratracheal administration of bleomycin was associated with severe progressive tissue fibrosis in the lung, characterized by the presence of myofibroblasts, fibroblast foci and significant extracellular accumulations of collagen and fibronectin [4].…”

“…Several studies suggest that IL-1b and IL-1Ra play a critical role in bleomycin-induced fibrosis in mice. Fibrosis is induced by IL-1b and neutralization of IL-1b by antibodies or specific blockage of the receptor IL-1R1 reduces the development of fibrosis [8]. In normal homeostasis, IL-1Ra production by alveolar macrophages is higher than the production of IL-1b.…”

Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis

“…9 Myofibroblasts extensively produce and secrete ECM proteins, 9 and are involved in abnormal wound repair and remodeling through various mechanisms, including deregulation of the balance between matrix metallopeptidases (MMPs) and tissue inhibitors of MMPs (TIMPs). 10 It was previously believed that the origin of myofibroblasts is solely peribronchiolar and perivascular fibroblasts that transdifferentiate to myofibroblasts in response to various stimuli, in particular TGF-b 1 . 11 However, recently, it was shown that lung epithelial cells undergo epithelial-mesenchymal transition (EMT) to become myofibroblasts after treatment with TGF-b 1 in vitro.…”

Therapeutic use of fisetin, curcumin, and mesoporous carbon nanoparticle loaded fisetin in bleomycin-induced idiopathic pulmonary fibrosis

“…Lung fibrosis induced by bleomycin delivered to animals via different routes has different pattern of foci distributions. Using the bleomycin-induced pulmonary fibrosis model, it has been previously reported that pulmonary inflammation and fibrosis are mediated by secretion of the proinflammatory and pro-fibrotic cytokine IL-1β through Nlrp3 inflammasome activation and IL-1R1/MyD88 signaling (Chen et al, 2015;Francois et al, 2015;Gasse et al, 2007). Fibrosis associated with bleomycin treatment has also been linked to toxic reactive oxygen and nitrogen species produced by infiltrating inflammatory cells (Yamazaki et al, 1998).…”