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-kappa B 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.
|Titolo:||IL-10 limits production of pathogenic TNF by M1 myeloid cells through induction of nuclear NF-kB p50 member in Trypanosoma congolense infection resistant C57BL/6 mice|
|Parole Chiave:||Inflammation; Inflammatory monocytes; Liver|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||nov-2011|
|Digital Object Identifier (DOI):||10.1002/eji.201041307|
|Appare nelle tipologie:||01 - Articolo su periodico|