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This work was supported by the Foundation for the National Institutes of Health Grants 1 U01 1U01HL145550 and 5R01HL123766-04. D.A.A.V. was supported by Foundation for the National Institutes of Health Grant P50CA097190. T.C. received the support of a fellowship from La Caixa Foundation (LCF/BQ/PI22/11910042). P.A.G. was supported by Foundation for the National Institutes of Health Grant 7F32CA261023-03. This project used the UPCI Cancer Biomarkers Facility: Luminex Core Laboratory, which was supported by Award P30CA047904.

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End-Stage Idiopathic Pulmonary Fibrosis Lung Microenvironment Promotes Impaired NK Activity

Publicat a:Journal Of Immunology. 211 (7): 1073-1081 - 2023-10-01 211(7), DOI: 10.4049/jimmunol.2300182

Autors: Cruz, T; Garcia, PAA; Chamucero-Millares, JA; Bondonese, A; Mitash, N; Sembrat, J; Tabib, T; Zhang, WP; Seyed, N; Peters, V; Stacey, S; Vignali, D; Mora, AL; Lafyatis, R; Rojas, M

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Idiopathic pulmonary fibrosis (IPF) is a fibrotic age-related chronic lung disease characterized by the accumulation of senescent cells. Whether impaired immune response is responsible for the accumulation of senescent cells in the IPF lung remains unknown. In this study, we characterized the NK phenotype in IPF lungs via flow cytometry using 5-dodecanoylaminofluorescein di-beta-D-galactopyranoside, markers of tissue residence, and chemokine receptors. The effect of the lung microenvironment was evaluated using lung fibroblast (LF) conditioned media (CM), and the bleomycin-induced pulmonary fibrosis mouse model was used to assess the in vivo relationship between NK cells and the accumulation of senescent cells. We found that NK cells from the lower lobe of IPF patients exhibited immune-senescent and impaired CD57(-)NKG2A(+) phenotype. We also observed that culture of NK cells from healthy donors in CM from IPF lower lobe lung fibroblasts induced a senescent-like phenotype and impaired cytotoxic capacity. There is an impaired NK recruitment by LF, and NKs presented decreased migration toward their CM. In addition, NK cell-depleted mice treated with bleomycin showed increased collagen deposition and accumulation of different populations of senescent cells compared with controls. The IPF lung microenvironment induces a dysfunctional NK phenotype limiting the clearance of lung senescent cells and the resolution of lung fibrosis. We propose that impaired NK activity could be one of the mechanisms responsible for perpetuating the accumulation of senescent cells in IPF lungs.

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