Pathogenic role for chemerin receptor CMKLR1 in experimental pulmonary fibrosis (P5138)

Abstract

Abstract Pulmonary fibrosis (PF) is a debilitating interstitial lung disease with few treatment options. The pathogenesis of idiopathic PF likely involves recurring microinjuries to the alveolar epithelium, leukocyte infiltration and inflammation, and an aberrant pro-fibrotic wound-healing response. CMKLR1 is a chemoattractant receptor for chemerin that is expressed on NK cells and other immune cells implicated in PF. Our goal was to determine the role of CMKLR1 in the pathogenesis of bleomycin-induced pulmonary inflammation and fibrosis. During the inflammatory phase of the model, neutrophilic infiltration of the airways was significantly increased in CMKLR1-deficient mice compared to wild-type (WT). During the fibrotic phase, CMKLR1-deficient mice developed more severe pulmonary fibrosis than WT as measured by lung collagen content and histopathology. The levels of key pro-inflammatory and pro-fibrotic cytokines (TNFα, IFNγ, IL-10, IL-17, and TGFβ) were significantly elevated in interstitial lung tissue from bleomycin-treated CMKRL1 KO mice. There was also a significant reduction in the recruitment of NK cells into the airways in CMKLR1 KO mice during the fibrotic phase. We hypothesize that chemerin and CMKLR1 play a protective role in lung fibrosis by dampening the initial inflammatory response and by recruiting anti-fibrotic leukocytes. Augmentation of the CMKLR1/chemerin system may therefore provide a novel approach to engage anti-fibrotic leukocytes for PF therapy.