title: IL-1α and complement cooperate in triggering local neutrophilic inflammation in response to adenovirus and eliminating virus-containing cells.
abstract: Inflammation is a highly coordinated host response to infection, injury, or cell stress. In most instances, the inflammatory response is pro-survival and is aimed at restoring physiological tissue homeostasis and eliminating invading pathogens, although exuberant inflammation can lead to tissue damage and death. Intravascular injection of adenovirus (Ad) results in virus accumulation in resident tissue macrophages that trigger activation of CXCL1 and CXCL2 chemokines via the IL-1α-IL-1RI signaling pathway. However, the mechanistic role and functional significance of this pathway in orchestrating cellular inflammatory responses to the virus in vivo remain unclear. Resident metallophilic macrophages expressing macrophage receptor with collagenous structure (MARCO+) in the splenic marginal zone (MZ) play the principal role in trapping Ad from the blood. Here we show that intravascular Ad administration leads to the rapid recruitment of Ly-6G+7/4+ polymorphonuclear leukocytes (PMNs) in the splenic MZ, the anatomical compartment that remains free of PMNs when these cells are purged from the bone marrow via a non-inflammatory stimulus. Furthermore, PMN recruitment in the splenic MZ resulted in elimination of virus-containing cells. IL-1α-IL-1RI signaling is only partially responsible for PMN recruitment in the MZ and requires CXCR2, but not CXCR1 signaling. We further found reduced recruitment of PMNs in the splenic MZ in complement C3-deficient mice, and that pre-treatment of IL-1α-deficient, but not wild-type mice, with complement inhibitor CR2-Crry (inhibits all complement pathways at C3 activation) or CR2-fH (inhibits only the alternative complement activation pathway) prior to Ad infection, abrogates PMN recruitment to the MZ and prevents elimination of MARCO+ macrophages from the spleen. Collectively, our study reveals a non-redundant role of the molecular factors of innate immunity--the chemokine-activating IL-1α-IL-1RI-CXCR2 axis and complement--in orchestrating local inflammation and functional cooperation of PMNs and resident macrophages in the splenic MZ, which collectively contribute to limiting disseminated pathogen spread via elimination of virus-containing cells.
authors.affiliation: Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Nelson C
authors.initials: NC
authors.lastname: Di Paolo
authors.affiliation: Division of Medical Genetics Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Baldwin
authors.affiliation: Division of Medical Genetics Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Irons
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.affiliation: Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Dmitry M
authors.initials: DM
authors.lastname: Shayakhmetov
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D053582:Interleukin-1alpha / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D018925:Chemokines; D053582:Interleukin-1alpha; D003165:Complement System Proteins