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

Gasse P. et al 2007.J. Clin. Invest.117;3786-3799.

Speaker: Peihua Wu (吳佩樺)                                   Time: 13:00-14:00, Dec 17, 2008

Commentator: Dr. Jiu-Yao Wang (王志堯)              Place: Room 601

Abstract:

      Idiopathic pulmonary fibrosis is characterized by scarring and thickening resulted from inflammation and fibrosis of the lung. The precise molecular mechanism in the initiation and progression of this disease remains unknown(1).  IL-1 family, such as IL-1β, alters the host response to an inflammatory, infectious, or immunological challenge. MyD88, the common adaptor of IL-1R1, IL-18R, and most TLR signaling pathway, is essentail in response to cell injury and development of chronic inflammation and fibrosis. The authors hypothesized the IL-1R1/MyD88 signaling mediates the connection between lung cell injury and pathological events such as collagen deposition. In the bleomycin(BLM)-induced lung injury model, the IL-1R1- and MyD88-deficient mice showed attenuated neutrophil infiltration, reduced production of lymphocyte chemotactic factors, and decreased lung fibrosis. Bone marrow transplantation disclosed that MyD88 signaling in this BLM model was mainly produced in radioresistant resident cells. Acute lung injury and fibrosis were induced with the exogonous IL-1β treatment, and futher reversed by IL-1R1- or MyD88-deficiency or IL-1 receptor antagonist(IL-1Ra). Additionally, the link between lung injury induced by BLM and IL-1R1/MyD88 signaling is likely through inflammasome, which has recently been demonstrated to sense stress and danger signals associated with cell injury(2). Mice deficient in adaptor protein ASC, which is essential in inflammasome function, exhibited attenuated inflammation in lung with BLM treatment. Taken together, the authors provide a critical mechanism mediated mainly by IL-1R1/MyD88 signaling in the progression of BLM-induced acute lung injury, and revealed IL-1Ra as a potential therapeutic agent for pulmonary inflammation and fibrosis.

Reference:

¹           Gross, T.J. & Hunninghake, G.W., Idiopathic pulmonary fibrosis. N Engl J Med 345 (7), 517-525 (2001).

²           Mariathasan, S. et al., Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440 (7081), 228-232 (2006).