title: IL-10 limits production of pathogenic TNF by M1 myeloid cells through induction of nuclear NF-κB p50 member in Trypanosoma congolense infection-resistant C57BL/6 mice.
abstract: A balance between parasite elimination and control of infection-associated pathogenicity is crucial for resistance to African trypanosomiasis. By producing TNF and NO, CD11b(+) myeloid cells with a classical activation status (M1) contribute to parasitemia control in experimental Trypanosoma congolense infection in resistant C57BL/6 mice. However, in these mice, IL-10 is required to regulate M1-associated inflammation, avoiding tissue/liver damage and ensuring prolonged survival. In an effort to dissect the mechanisms behind the anti-inflammatory activity of IL-10 in T. congolense-infected C57BL/6 mice, we show, using an antibody blocking the IL-10 receptor, that IL-10 impairs the accumulation and M1 activation of TNF/iNOS-producing CD11b(+) Ly6C(+) cells in the liver. Using infected IL-10(flox/flox) LysM-Cre(+/+) mice, we show that myeloid cell-derived IL-10 limits M1 activation of CD11b(+) Ly6C(+) cells specifically at the level of TNF production. Moreover, higher production of TNF in infected IL-10(flox/flox) LysM-Cre(+/+) mice is associated with reduced nuclear accumulation of the NF-κB p50 subunit in CD11b(+) M1 cells. Furthermore, in infected p50(-/-) mice, TNF production by CD11b(+) Ly6C(+) cells and liver injury increases. These data suggest that preferential nuclear accumulation of p50 represents an IL-10-dependent anti-inflammatory mechanism in M1-type CD11b(+) myeloid cells that regulates the production of pathogenic TNF during T. congolense infection in resistant C57BL/6 mice.
authors.affiliation: Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Bosschaerts
authors.forename: Yannick
authors.initials: Y
authors.lastname: Morias
authors.forename: Benoît
authors.initials: B
authors.lastname: Stijlemans
authors.forename: Michel
authors.initials: M
authors.lastname: Hérin
authors.forename: Chiara
authors.initials: C
authors.lastname: Porta
authors.forename: Antonio
authors.initials: A
authors.lastname: Sica
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Patrick
authors.initials: P
authors.lastname: De Baetselier
authors.forename: Alain
authors.initials: A
authors.lastname: Beschin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D005434:Flow Cytometry; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014348:Trypanosoma congolense / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D052002:NF-kappa B p50 Subunit; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10