title: The triggering receptor expressed on myeloid cells 2 inhibits complement component 1q effector mechanisms and exerts detrimental effects during pneumococcal pneumonia.
abstract: Phagocytosis and inflammation within the lungs is crucial for host defense during bacterial pneumonia. Triggering receptor expressed on myeloid cells (TREM)-2 was proposed to negatively regulate TLR-mediated responses and enhance phagocytosis by macrophages, but the role of TREM-2 in respiratory tract infections is unknown. Here, we established the presence of TREM-2 on alveolar macrophages (AM) and explored the function of TREM-2 in the innate immune response to pneumococcal infection in vivo. Unexpectedly, we found Trem-2(-/-) AM to display augmented bacterial phagocytosis in vitro and in vivo compared to WT AM. Mechanistically, we detected that in the absence of TREM-2, pulmonary macrophages selectively produced elevated complement component 1q (C1q) levels. We found that these increased C1q levels depended on peroxisome proliferator-activated receptor-δ (PPAR-δ) activity and were responsible for the enhanced phagocytosis of bacteria. Upon infection with S. pneumoniae, Trem-2(-/-) mice exhibited an augmented bacterial clearance from lungs, decreased bacteremia and improved survival compared to their WT counterparts. This work is the first to disclose a role for TREM-2 in clinically relevant respiratory tract infections and demonstrates a previously unknown link between TREM-2 and opsonin production within the lungs.
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Omar
authors.initials: O
authors.lastname: Sharif
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Riem
authors.initials: R
authors.lastname: Gawish
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Warszawska
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Rui
authors.initials: R
authors.lastname: Martins
authors.affiliation: Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Lakovits
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Anastasiya
authors.initials: A
authors.lastname: Hladik
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Bianca
authors.initials: B
authors.lastname: Doninger
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Brunner
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ana
authors.initials: A
authors.lastname: Korosec
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Roland E
authors.initials: RE
authors.lastname: Schwarzenbacher
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Tiina
authors.initials: T
authors.lastname: Berg
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Mesteri
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Gilfillan
authors.affiliation: Department of Clinical Neurosciences, Istituto Nazionale Neurologico Carlo Besta, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Salmaggi
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany.
authors.forename: Admar
authors.initials: A
authors.lastname: Verschoor
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D047495:PPAR gamma / Q000378:metabolism; D010587:Phagocytosis; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D047495:PPAR gamma; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D015922:Complement C1q