title: Lipoxin Signaling in Murine Lung Host Responses to Cryptococcus neoformans Infection.
abstract: Lipoxins (LX) are proresolving mediators that augment host defense against bacterial infection. Here, we investigated roles for LX in lung clearance of the fungal pathogen Cryptococcus neoformans (Cne). After intranasal inoculation of 5,000 CFU Cne, C57BL/6 and C.B-17 mice exhibited strain-dependent differences in Cne clearance, immunologic responses, and lipoxin A4 (LXA4) formation and receptor (ALX/FPR2) expression. Compared with C.B-17 mice, C57BL/6 lungs had increased and persistent Cne infection 14 days after inoculation, increased eosinophils, and distinct profiles of inflammatory cytokines. Relative to C.B-17 mice, bronchoalveolar lavage fluid levels of LXA4 were increased before and after infection in C57BL/6. The kinetics for 15-epi-LXA4 production were similar in both strains. Lung basal expression of the LX biosynthetic enzyme Alox12/15 (12/15-lipoxygenase) was increased in C57BL/6 mice and further increased after Cne infection. In contrast, lung basal expression of the LXA4 receptor Alx/Fpr2 was higher in C.B-17 relative to C57BL/6 mice, and after Cne infection, Alx/Fpr2 expression was significantly increased in only C.B-17 mice. Heat-killed Cne initiated lung cell generation of IFN-γ and IL-17 and was further increased in C.B-17 mice by 15-epi-LXA4. A trend toward reduced Cne clearance and IFN-γ production was observed upon in vivo administration of an ALX/FPR2 antagonist. Together, these findings provide the first evidence that alterations in cellular immunity against Cne are associated with differences in LXA4 production and receptor expression, suggesting an important role for ALX/FPR2 signaling in the regulation of pathogen-mediated inflammation and antifungal lung host defense.
authors.affiliation: 1 Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Jennifer K
authors.identifier: http://orcid.org/0000-0003-1656-2633
authors.initials: JK
authors.lastname: Colby
authors.affiliation: 2 Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Gott
authors.affiliation: 2 Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Wilder
authors.affiliation: 1 Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002634:Chemotaxis, Leukocyte; D003453:Cryptococcosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000276:immunology / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007700:Kinetics; D044045:Lipoxins / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity
chemical_list: C475064:12-15-lipoxygenase; D020381:Interleukin-17; D044045:Lipoxins; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse; C040527:lipoxin A4; C509690:tryptophyl-arginyl-tryptophyl-tryptophyl-tryptophyl-tryptophanamide; D007371:Interferon-gamma; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: ALX/FPR2; Cryptococcus neoformans; lipoxin A4; pneumonia; resolution