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

✍ Scribed by Tom Bosschaerts; Yannick Morias; Benoît Stijlemans; Michel Hérin; Chiara Porta; Antonio Sica; Alberto Mantovani; Patrick De Baetselier; Alain Beschin

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 527 KB
• Volume: 41
• Category: Article
• ISSN: 0014-2980
• DOI: 10.1002/eji.201041307

✦ Synopsis

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.