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Dendritic cells (DCs) and macrophages (M\u03a6) are critical antigen\u2010presenting cells (APCs) that direct adaptive immunity. However, the role of CD11c+ myeloid cells in lung extracellular matrix (ECM) accumulation and pulmonary fibrosis is poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We aimed to investigate the impact of depleting CD11c+ myeloid cells, including DCs and macrophages, during bleomycin\u2010induced pulmonary fibrosis in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used a diphtheria toxin (DTx) receptor (DTR) transgenic mouse model (CD11c\u2010DTR\u2010Tg) to deplete CD11c+ myeloid cells through two methods: Systemic Depletion (SD) via intraperitoneal injection (i.p.) and local depletion (LD) via intranasal instillation (i.n.). We then assessed the effects of CD11c+ cell depletion during bleomycin\u2010induced lung inflammation and fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fourteen days after bleomycin instillation, there was a progressive accumulation of myeloid cells, specifically F4\/80\u2010MHCII+CD11c+ DCs and F4\/80\u2009+\u2009MHCII+CD11c+ M\u03a6, preceding mortality and pulmonary fibrosis. Systemic depletion of CD11c+ DCs and M\u03a6 via i.p. DTx administration in CD11c\u2010DTR\u2010Tg mice protected against bleomycin\u2010induced mortality and pulmonary fibrosis compared to wild\u2010type (WT) mice. Systemic depletion reduced myeloid cells, airway inflammation (total leukocytes, neutrophils, and CD4+ lymphocytes in bronchoalveolar lavage (BAL), inflammatory and fibrogenic mediators, and fibrosis\u2010related mRNAs (Collagen\u20101\u03b11 and \u03b1\u2010SMA). Increased anti\u2010inflammatory cytokine IL\u201010 and CXCL9 levels were observed, resulting in lower lung hydroxyproline content and Ashcroft fibrosis score. Conversely, local depletion of CD11c+ cells increased mortality by acute leukocyte influx (predominantly neutrophils, DCs, and M\u03a6 in BAL) correlated to IL\u20101\u03b2, with lung hyper\u2010inflammation and early fibrosis development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Systemic depletion of CD11c+ cells confers protection against inflammation and fibrosis induced by Bleomycin, underscoring the significance of myeloid cells expressing F4\/80\u2010MHCII+CD11c+ DCs and F4\/80\u2009+\u2009MHCII+CD11c+ M\u03a6 orchestrating the inflammatory milieu within the lungs, potentially as a source of cytokines sustaining pulmonary chronic inflammation leading to progressive fibrosis and mortality.<\/jats:p>\n                  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