title: Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decline in lung function, caused by exposure to exogenous particles, mainly cigarette smoke (CS). COPD is initiated and perpetuated by an abnormal CS-induced inflammatory response of the lungs, involving both innate and adaptive immunity. Specifically, B cells organized in iBALT structures and macrophages accumulate in the lungs and contribute to CS-induced emphysema, but the mechanisms thereof remain unclear. Here, we demonstrate that B cell-deficient mice are significantly protected against CS-induced emphysema. Chronic CS exposure led to an increased size and number of iBALT structures, and increased lung compliance and mean linear chord length in wild-type (WT) but not in B cell-deficient mice. The increased accumulation of lung resident macrophages around iBALT and in emphysematous alveolar areas in CS-exposed WT mice coincided with upregulated MMP12 expression. In vitro coculture experiments using B cells and macrophages demonstrated that B cell-derived IL-10 drives macrophage activation and MMP12 upregulation, which could be inhibited by an anti-IL-10 antibody. In summary, B cell function in iBALT formation seems necessary for macrophage activation and tissue destruction in CS-induced emphysema and possibly provides a new target for therapeutic intervention in COPD.
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany;
authors.forename: Gerrit
authors.initials: G
authors.lastname: John-Schuster
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany;
authors.forename: Katrin
authors.initials: K
authors.lastname: Hager
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany;
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Conlon
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany; Experimental Genetics, Technical University Munich, Freising-Weihenstephan, Germany; and.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany; Klinikum der Universität München, Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research, Neuherberg, Germany; oender.yildirim@helmholtz-muenchen.de.
authors.forename: Ali Önder
authors.initials: AÖ
authors.lastname: Yildirim
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010196:Pancreatic Elastase; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012129:Respiratory Function Tests; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D000906:Antibodies; D014028:Tobacco Smoke Pollution; D016753:Interleukin-10; D010196:Pancreatic Elastase; D053508:Matrix Metalloproteinase 12
keywords: B cells; COPD; IL-10; iBALT; macrophages