title: Selenoprotein Expression in Macrophages Is Critical for Optimal Clearance of Parasitic Helminth Nippostrongylus brasiliensis.
abstract: The plasticity of macrophages is evident in helminthic parasite infections, providing protection from inflammation. Previously we demonstrated that the micronutrient selenium induces a phenotypic switch in macrophage activation from a classically activated (pro-inflammatory; M1/CAM) toward an alternatively activated (anti-inflammatory; M2/AAM) phenotype, where cyclooxygenase (COX)-dependent cyclopentenone prostaglandin J2 (15d-PGJ2) plays a key role. Here, we hypothesize that dietary selenium modulates macrophage polarization toward an AAM phenotype to assist in the increasing clearance of adult Nippostrongylus brasiliensis, a gastrointestinal nematode parasite. Mice on a selenium-adequate (0.08 ppm) diet significantly augmented intestinal AAM presence while decreasing adult worms and fecal egg production when compared with infection of mice on selenium-deficient (<0.01 ppm) diet. Further increase in dietary selenium to supraphysiological levels (0.4 ppm) had very little or no impact on worm expulsion. Normal adult worm clearance and enhanced AAM marker expression were observed in the selenium-supplemented Trsp(fl/fl)Cre(WT) mice that express selenoproteins driven by tRNA(Sec) (Trsp), whereas N. brasiliensis-infected Trsp(fl/fl)Cre(LysM) selenium-supplemented mice showed a decreased clearance, with lowered intestinal expression of several AAM markers. Inhibition of the COX pathway with indomethacin resulted in delayed worm expulsion in selenium-adequate mice. This was rescued with 15d-PGJ2, which partially recapitulated the effect of selenium supplementation on fecal egg output in addition to increasing markers of AAMs in the small intestine. Antagonism of PPARγ blocked the effect of selenium. These results suggest that optimal expression of selenoproteins and selenium-dependent production of COX-derived endogenous prostanoids, such as Δ(12)-PGJ2 and 15d-PGJ2, may regulate AAM activation to enhance anti-helminthic parasite responses.
authors.affiliation: From the Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, Division of Cancer Epidemiology and Genetics, NCI, National Institutes of Health, Rockville, Maryland 20850.
authors.forename: Shakira M
authors.initials: SM
authors.lastname: Nelson
authors.affiliation: From the Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Shay
authors.affiliation: From the Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Jamaal L
authors.initials: JL
authors.lastname: James
authors.affiliation: Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, NCI, National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, Maryland 20705.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.affiliation: From the Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, ksprabhu@psu.edu.
authors.forename: K Sandeep
authors.initials: KS
authors.lastname: Prabhu
mesh_terms: D000818:Animals; D019587:Dietary Supplements; D005786:Gene Expression Regulation / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D009559:Nippostrongylus / Q000276:immunology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000276:immunology; D012643:Selenium / Q000494:pharmacology; D051140:Selenoproteins / Q000276:immunology*; D017206:Strongylida Infections / Q000188:drug therapy / Q000276:immunology*
chemical_list: C477819:15-deoxyprostaglandin J2; D051140:Selenoproteins; C499810:delta(12)-prostaglandin J(2); D012643:Selenium; D015230:Prostaglandin D2
keywords: inflammation; macrophage; parasite; prostaglandin; resolution of inflammation; selenium; selenoprotein