title: Alternatively activated myeloid cells limit pathogenicity associated with African trypanosomiasis through the IL-10 inducible gene selenoprotein P.
abstract: Uncontrolled inflammation is a major cause of tissue injury/pathogenicity often resulting in death of a host infected with African trypanosomes. Thus, comparing the immune response in hosts that develop different degrees of disease severity represents a promising approach to discover processes contributing to trypanosomiasis control. It is known that limitation of pathogenicity requires a transition in the course of infection, from an IFN-gamma-dependent response resulting in the development of classically activated myeloid cells (M1), to a counterbalancing IL-10-dependent response associated with alternatively activated myeloid cells (M2). Herein, mechanisms and downstream effectors by which M2 contribute to lower the pathogenicity and the associated susceptibility to African trypanosomiasis have been explored. Gene expression analysis in IL-10 knockout and wild-type mice, that are susceptible and relatively resistant to Trypanosoma congolense infection, respectively, revealed a number of IL-10-inducible genes expressed by M2, including Sepp1 coding for selenoprotein P. Functional analyses confirm that selenoprotein P contributes to limit disease severity through anti-oxidant activity. Indeed, Sepp1 knockout mice, but not Sepp1(Delta)(240-361) mice retaining the anti-oxidant motif but lacking the selenium transporter domain of selenoprotein P, exhibited increased tissue injury that associated with increased production of reactive oxygen species and increased apoptosis in the liver immune cells, reduced parasite clearance capacity of myeloid cells, and decreased survival. These data validate M2-associated molecules as functioning in reducing the impact of parasite infection on the host.
authors.affiliation: Department of Molecular and Cellular Interactions, Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, Brussels, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Bosschaerts
authors.forename: Martin
authors.initials: M
authors.lastname: Guilliams
authors.forename: Wim
authors.initials: W
authors.lastname: Noel
authors.forename: Michel
authors.initials: M
authors.lastname: Hérin
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Burk
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Hill
authors.forename: Lea
authors.initials: L
authors.lastname: Brys
authors.forename: Geert
authors.initials: G
authors.lastname: Raes
authors.forename: Gholamreza Hassanzadeh
authors.initials: GH
authors.lastname: Ghassabeh
authors.forename: Patrick
authors.initials: P
authors.lastname: De Baetselier
authors.forename: Alain
authors.initials: A
authors.lastname: Beschin
mesh_terms: D000818:Animals; D000975:Antioxidants; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000469:parasitology; D017434:Protein Structure, Tertiary / Q000235:genetics; D017382:Reactive Oxygen Species / Q000276:immunology; D051149:Selenoprotein P / Q000235:genetics / Q000276:immunology*; D014348:Trypanosoma congolense / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000235:genetics / Q000276:immunology*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D051149:Selenoprotein P; D016753:Interleukin-10