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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 (ATF6\u03b1), 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 <jats:italic>Atf6\u03b1<\/jats:italic> in IPF patients\u2019 lung single\u2010cell RNA sequencing dataset, archived surgical lung specimens, and CD14<jats:sup>+<\/jats:sup> circulating monocytes. To assess the impact of ATF6\u03b1 on pulmonary macrophage composition and pro\u2010fibrotic function during tissue remodeling, we conducted an <jats:italic>in vivo<\/jats:italic> myeloid\u2010specific deletion of <jats:italic>Atf6\u03b1<\/jats:italic>. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL\/6 and myeloid specific ATF6\u03b1\u2010deficient mice in the context of bleomycin\u2010induced lung injury. Our results demonstrated that <jats:italic>Atf6\u03b1<\/jats:italic> mRNA was expressed in pro\u2010fibrotic macrophages found in the lung of a patient with IPF and in CD14<jats:sup>+<\/jats:sup> circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid\u2010specific deletion of <jats:italic>Atf6\u03b1<\/jats:italic> altered the pulmonary macrophage composition, expanding CD11b<jats:sup>+<\/jats:sup> subpopulations with dual polarized CD38<jats:sup>+<\/jats:sup>CD206<jats:sup>+<\/jats:sup> expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic <jats:italic>ex vivo<\/jats:italic> investigation revealed that ATF6\u03b1 was required for CHOP induction and the death of bone marrow\u2010derived macrophages. Overall, our findings suggest a detrimental role for the ATF6\u03b1\u2010deficient CD11b<jats:sup>+<\/jats:sup> macrophages which had altered function during lung injury and fibrosis.<\/jats:p>","DOI":"10.1111\/imcb.12637","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T14:09:36Z","timestamp":1677766176000},"page":"412-427","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Myeloid\u2010specific deletion of activating transcription factor 6 alpha increases <scp>CD11b<\/scp><sup>+<\/sup> macrophage subpopulations and aggravates lung fibrosis"],"prefix":"10.1111","volume":"101","author":[{"given":"Olivia","family":"Mekhael","sequence":"first","affiliation":[{"name":"Medical Sciences Graduate Program McMaster University  Hamilton Ontario 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