title: mCLCA3 modulates IL-17 and CXCL-1 induction and leukocyte recruitment in murine Staphylococcus aureus pneumonia.
abstract: The human hCLCA1 and its murine ortholog mCLCA3 (calcium-activated chloride channel regulators) are exclusively expressed in mucus cells and linked to inflammatory airway diseases with increased mucus production, such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Both proteins have a known impact on the mucus cell metaplasia trait in these diseases. However, growing evidence points towards an additional role in innate immune responses. In the current study, we analyzed Staphylococcus aureus pneumonia, an established model to study pulmonary innate immunity, in mCLCA3-deficient and wild-type mice, focusing on the cellular and cytokine-driven innate inflammatory response. We compared clinical signs, bacterial clearance, leukocyte immigration and cytokine responses in the bronchoalveolar compartment, as well as pulmonary vascular permeability, histopathology, mucus cell number and mRNA expression levels of selected genes (mClca1 to 7, Muc5ac, Muc5b, Muc2, Cxcl-1, Cxcl-2, Il-17). Deficiency of mCLCA3 resulted in decreased neutrophilic infiltration into the bronchoalveolar space during bacterial infection. Only the cytokines IL-17 and the murine CXCL-8 homolog CXCL-1 were decreased on mRNA and protein levels during bacterial infection in mCLCA3-deficient mice compared to wild-type controls. However, no differences in clinical outcome, histopathology or mucus cell metaplasia were observed. We did not find evidence for regulation of any other CLCA homolog that would putatively compensate for the lack of mCLCA3. In conclusion, mCLCA3 appears to modulate leukocyte response via IL-17 and murine CXCL-8 homologs in acute Staphylococcus aureus pneumonia which is well in line with the proposed function of hCLCA1 as a signaling molecule acting on alveolar macrophages.
authors.affiliation: Department of Veterinary Pathology, Freie Universität, Berlin, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Dietert
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Reppe
authors.affiliation: Department of Veterinary Pathology, Freie Universität, Berlin, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Mundhenk
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.affiliation: Department of Veterinary Pathology, Freie Universität, Berlin, Germany.
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002199:Capillary Permeability / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054360:Chemokine CXCL1 / Q000096:biosynthesis* / Q000276:immunology; D018118:Chloride Channels / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009077:Mucins / Q000096:biosynthesis; D009088:Mucoproteins / Q000235:genetics / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011023:Pneumonia, Staphylococcal / Q000276:immunology* / Q000382:microbiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D013203:Staphylococcal Infections / Q000276:immunology / Q000382:microbiology; D013211:Staphylococcus aureus / Q000254:growth & development / Q000276:immunology*
chemical_list: D054360:Chemokine CXCL1; D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D020381:Interleukin-17; D009077:Mucins; D009088:Mucoproteins; D012333:RNA, Messenger