title: Acute-phase protein hemopexin is a negative regulator of Th17 response and experimental autoimmune encephalomyelitis development.
abstract: Hemopexin (Hx) is an acute-phase protein synthesized by hepatocytes in response to the proinflammatory cytokines IL-6, IL-1β, and TNF-α. Hx is the plasma protein with the highest binding affinity to heme and controls heme-iron availability in tissues and also in T lymphocytes, where it modulates their responsiveness to IFN-γ. Recent data have questioned regarding an anti-inflammatory role of Hx, a role that may be both heme-binding dependent and independent. The aim of this study was to investigate the role of Hx in the development of a T cell-mediated inflammatory autoimmune response. During experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis, Hx content in serum increased and remained high. When EAE was induced in Hx knockout (Hx(-/-)) mice, they developed a clinically earlier and exacerbated EAE compared with wild-type mice, associated to a higher amount of CD4(+)-infiltrating T cells. The severe EAE developed by Hx(-/-) mice could be ascribed to an enhanced expansion of Th17 cells accounting for both a higher disposition of naive T cells to differentiate toward the Th17 lineage and a higher production of Th17 differentiating cytokines IL-6 and IL-23 by APCs. When purified human Hx was injected in Hx(-/-) mice before EAE induction, Th17 expansion, as well as disease severity, were comparable with those of wild-type mice. Taken together, these data indicate that Hx has a negative regulatory role in Th17-mediated inflammation and prospect its pharmacological use to limit the expansion of this cell subset in inflammatory and autoimmune disease.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy;
authors.forename: Simona
authors.initials: S
authors.lastname: Rolla
authors.forename: Giada
authors.initials: G
authors.lastname: Ingoglia
authors.forename: Valentina
authors.initials: V
authors.lastname: Bardina
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tolosano
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D006466:Hemopexin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D022781:Hepatocytes / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007165:Immunosuppression Therapy; D018836:Inflammation Mediators / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D006466:Hemopexin