title: Loss of CCR2 signaling alters leukocyte recruitment and exacerbates γ-herpesvirus-induced pneumonitis and fibrosis following bone marrow transplantation.
abstract: CCR2-expressing leukocytes are required for the progression of fibrosis in models of induced lung injury as well as models of bone marrow transplant (BMT)-related idiopathic pneumonia syndrome. Infection with murid γ-herpesvirus-68 (γHV-68) results in severe pneumonitis and pulmonary fibrosis following syngeneic BMT; however, the roles that various proinflammatory leukocyte populations play in this process remain unclear. Deletion of CCR2 in both non-BMT and BMT mice increased early lytic viral replication and resulted in a reduction in the numbers of lung-infiltrating GR1+,F4/80+ and CXCR1+ cells, while maintaining robust neutrophil infiltration. Similarly, in γHV-68-infected CCR2(-/-) BMT mice, recruitment of monocytes and lymphocytes were reduced whereas neutrophil recruitment was increased compared with wild-type (WT) BMT mice. Interestingly, levels of profibrotic IL-17 were increased in infected CCR2 BMT mice compared with WT BMT. Furthermore, an increase in lung-associated collagen was detected even though there was an overall decrease in the number of profibrotic CCR2+ fibrocytes detected in the lungs of CCR2(-/-) BMT mice. These data indicate that, contrary to most models of fibrosis, deletion of CCR2 offers no protection from γ-herpesvirus-induced pneumonitis and fibrosis, and, indeed, CCR2+ cells play a suppressive role during the development of pulmonary fibrosis following γ-herpesvirus infection post-BMT by limiting IL-7 and collagen production.
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan; sgurczyn@umich.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gurczynski
authors.affiliation: Graduate Program in Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Procario
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan;
authors.forename: David N
authors.initials: DN
authors.lastname: O'Dwyer
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan;
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wilke
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bethany B
authors.identifier: 0000-0003-3051-745X
authors.initials: BB
authors.lastname: Moore
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D018142:Gammaherpesvirinae / Q000276:immunology; D006566:Herpesviridae Infections / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D011024:Pneumonia, Viral / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D054390:Receptors, CCR2 / Q000502:physiology*; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2
keywords: BMT; CCR2; IL17; fibrosis; herpesvirus