title: Tip-DC development during parasitic infection is regulated by IL-10 and requires CCL2/CCR2, IFN-gamma and MyD88 signaling.
abstract: The development of classically activated monocytic cells (M1) is a prerequisite for effective elimination of parasites, including African trypanosomes. However, persistent activation of M1 that produce pathogenic molecules such as TNF and NO contributes to the development of trypanosome infection-associated tissue injury including liver cell necrosis in experimental mouse models. Aiming to identify mechanisms involved in regulation of M1 activity, we have recently documented that during Trypanosoma brucei infection, CD11b(+)Ly6C(+)CD11c(+) TNF and iNOS producing DCs (Tip-DCs) represent the major pathogenic M1 liver subpopulation. By using gene expression analyses, KO mice and cytokine neutralizing antibodies, we show here that the conversion of CD11b(+)Ly6C(+) monocytic cells to pathogenic Tip-DCs in the liver of T. brucei infected mice consists of a three-step process including (i) a CCR2-dependent but CCR5- and Mif-independent step crucial for emigration of CD11b(+)Ly6C(+) monocytic cells from the bone marrow but dispensable for their blood to liver migration; (ii) a differentiation step of liver CD11b(+)Ly6C(+) monocytic cells to immature inflammatory DCs (CD11c(+) but CD80/CD86/MHC-II(low)) which is IFN-gamma and MyD88 signaling independent; and (iii) a maturation step of inflammatory DCs to functional (CD80/CD86/MHC-II(high)) TNF and NO producing Tip-DCs which is IFN-gamma and MyD88 signaling dependent. Moreover, IL-10 could limit CCR2-mediated egression of CD11b(+)Ly6C(+) monocytic cells from the bone marrow by limiting Ccl2 expression by liver monocytic cells, as well as their differentiation and maturation to Tip-DCs in the liver, showing that IL-10 works at multiple levels to dampen Tip-DC mediated pathogenicity during T. brucei infection. A wide spectrum of liver diseases associates with alteration of monocyte recruitment, phenotype or function, which could be modulated by IL-10. Therefore, investigating the contribution of recruited monocytes to African trypanosome induced liver injury could potentially identify new targets to treat hepatic inflammation in general, and during parasite infection in particular.
authors: Department of Molecular and Cellular Interactions, VIB, Brussels, Belgium.
authors: Tom
authors: T
authors: Bosschaerts
authors: Martin
authors: M
authors: Guilliams
authors: Benoît
authors: B
authors: Stijlemans
authors: Yannick
authors: Y
authors: Morias
authors: Daniel
authors: D
authors: Engel
authors: Frank
authors: F
authors: Tacke
authors: Michel
authors: M
authors: Hérin
authors: Patrick
authors: P
authors: De Baetselier
authors: Alain
authors: A
authors: Beschin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D018932:Chemokine CCL2 / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D054390:Receptors, CCR2 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014346:Trypanosoma brucei brucei / Q000276:immunology; D014352:Trypanosomiasis / Q000276:immunology*
chemical_list: D018932:Chemokine CCL2; D053594:Myeloid Differentiation Factor 88; D054390:Receptors, CCR2; D016753:Interleukin-10; D007371:Interferon-gamma