title: Lipocalin 2 regulates inflammation during pulmonary mycobacterial infections.
abstract: Pulmonary tuberculosis (TB), caused by the intracellular bacteria Mycobacterium tuberculosis, is a worldwide disease that continues to kill more than 1.5 million people every year worldwide. The accumulation of lymphocytes mediates the formation of the tubercle granuloma in the lung and is crucial for host protection against M.tuberculosis infection. However, paradoxically the tubercle granuloma is also the basis for the immunopathology associated with the disease and very little is known about the regulatory mechanisms that constrain the inflammation associated with the granulomas. Lipocalin 2 (Lcn2) is a member of the lipocalin family of proteins and binds to bacterial siderophores thereby sequestering iron required for bacterial growth. Thus far, it is not known whether Lcn2 plays a role in the inflammatory response to mycobacterial pulmonary infections. In the present study, using models of acute and chronic mycobacterial pulmonary infections, we reveal a novel role for Lcn2 in constraining T cell lymphocytic accumulation and inflammation by inhibiting inflammatory chemokines, such as CXCL9. In contrast, Lcn2 promotes neutrophil recruitment during mycobacterial pulmonary infection, by inducing G-CSF and KC in alveolar macrophages. Importantly, despite a common role for Lcn2 in regulating chemokines during mycobacterial pulmonary infections, Lcn2 deficient mice are more susceptible to acute M.bovis BCG, but not low dose M.tuberculosis pulmonary infection.
authors.affiliation: Division of Pulmonary Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Guglani
authors.forename: Radha
authors.initials: R
authors.lastname: Gopal
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.forename: Beth Fallert
authors.initials: BF
authors.lastname: Junecko
authors.forename: Yinyao
authors.initials: Y
authors.lastname: Lin
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berger
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
authors.forename: Troy D
authors.initials: TD
authors.lastname: Randall
authors.forename: Todd A
authors.initials: TA
authors.lastname: Reinhart
authors.forename: Yvonne R
authors.initials: YR
authors.lastname: Chan
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D000208:Acute Disease; D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002465:Cell Movement; D054370:Chemokine CXCL9 / Q000037:antagonists & inhibitors / Q000276:immunology; D002908:Chronic Disease; D015870:Gene Expression; D015769:Granuloma, Respiratory Tract / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000662:veterinary*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000662:veterinary; D007501:Iron / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009164:Mycobacterium Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000662:veterinary*; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D017262:Siderophores / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000662:veterinary*
chemical_list: D000209:Acute-Phase Proteins; D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D017262:Siderophores; C071332:Lcn2 protein, mouse; D007501:Iron