Myeloid‐specific deletion of activating transcription factor 6 alpha increases CD11b+ macrophage subpopulations and aggravates lung fibrosis

• Published in: Immunology and cell biology 2023-05, Vol.101 (5), p.412-427
• Main Authors: Mekhael, Olivia, Revill, Spencer D, Hayat, Aaron I, Cass, Steven P, MacDonald, Kyle, Vierhout, Megan, Ayoub, Anmar, Reihani, Amir, Padwal, Manreet, Imani, Jewel, Ayaub, Ehab, Yousof, Tamana, Dvorkin‐Gheva, Anna, Rullo, Anthony, Hirota, Jeremy A, Richards, Carl D, Bridgewater, Darren, Stämpfli, Martin R, Hambly, Nathan, Naqvi, Asghar, Kolb, Martin RJ, Ask, Kjetil
• Format: Article
• Language: English
• Subjects: Activating transcription factor 6; Activating Transcription Factor 6 - metabolism; Animals; ATF6α, CHOP, endoplasmic reticulum stress, macrophage, myeloid‐derived cells, unfolded protein response; Bleomycin; Bleomycin - adverse effects; Bleomycin - metabolism; CD11b antigen; CD14 antigen; CD38 antigen; Cell activation; Collagen; Fibrosis; Flow cytometry; Idiopathic Pulmonary Fibrosis - pathology; Lung - pathology; Lung diseases; Lung Injury - metabolism; Macrophages; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Monocytes; Protein folding; Pulmonary fibrosis; Transcription factors
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1111/imcb.12637

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients’ lung single‐cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro‐fibrotic function during tissue remodeling, we conducted an in vivo myeloid‐specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α‐deficient mice in the context of bleomycin‐induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro‐fibrotic macrophages found in the lung of a patient with IPF and in CD14+ circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid‐specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow‐derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α‐deficient CD11b+ macrophages which had altered function during lung injury and fibrosis. In this article, we show that during bleomycin‐induced tissue remodeling, the myeloid‐specific deletion of Atf6α expanded CD11b+ subpopulations with dual polarized CD38+CD206+ expressing macrophages. This expansion was associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and for the apoptotic death of bone marrow‐derived CD11b+ macrophages. Overall, these data show that the myeloid‐specific deletion of Atf6α alters macrophage composition and function impairing tissue