IRAK-M Regulates Monocyte Trafficking to the Lungs in Response to Bleomycin Challenge.

Brenda F Reader, Shruthi Sethuraman, Bryan R Hay, Rose Viguna Thomas Becket, Manjula Karpurapu, Sangwoon Chung, Yong Gyu Lee, John W Christman, Megan N Ballinger

Journal of immunology (Baltimore, Md. : 1950) 2020 May 15

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Idiopathic pulmonary fibrosis is a deadly disease characterized by excessive extracellular matrix deposition in the lungs, resulting in decreased pulmonary function. Although epithelial cells and fibroblasts have long been the focus of idiopathic pulmonary fibrosis research, the role of various subpopulations of macrophages in promoting a fibrotic response is an emerging target. Healthy lungs are composed of two macrophage populations, tissue-resident alveolar macrophages and interstitial macrophages, which help to maintain homeostasis. After injury, tissue-resident alveolar macrophages are depleted, and monocytes from the bone marrow (BM) traffic to the lungs along a CCL2/CCR2 axis and differentiate into monocyte-derived alveolar macrophages (Mo-AMs), which is a cell population implicated in murine models of pulmonary fibrosis. In this study, we sought to determine how IL-1R-associated kinase-M (IRAK-M), a negative regulator of TLR signaling, modulates monocyte trafficking into the lungs in response to bleomycin. Our data indicate that after bleomycin challenge, mice lacking IRAK-M have decreased monocyte trafficking and reduced Mo-AMs in their lungs. Although IRAK-M expression did not regulate differences in chemokines, cytokines, or adhesion molecules associated with monocyte recruitment, IRAK-M was necessary for CCR2 upregulation following bleomycin challenge. This finding prompted us to develop a competitive BM chimera model, which demonstrated that expression of BM-derived IRAK-M was necessary for monocyte trafficking into the lung and for subsequent enhanced collagen deposition. These data indicate that IRAK-M regulates monocyte trafficking by increasing the expression of CCR2, resulting in enhanced monocyte translocation into the lung, Mo-AM differentiation, and development of pulmonary fibrosis. Copyright © 2020 by The American Association of Immunologists, Inc.

Citation

Brenda F Reader, Shruthi Sethuraman, Bryan R Hay, Rose Viguna Thomas Becket, Manjula Karpurapu, Sangwoon Chung, Yong Gyu Lee, John W Christman, Megan N Ballinger. IRAK-M Regulates Monocyte Trafficking to the Lungs in Response to Bleomycin Challenge. Journal of immunology (Baltimore, Md. : 1950). 2020 May 15;204(10):2661-2670