The role of interleukin-10 and monocytic cells in liver pathogenicity during African trypanosome infection.

During both natural and experimental infections with African trypanosomes, different host?parasite combinations lead to different degrees of disease severity. To unravel the mechanisms underlying infection?associated pathogenicity including liver injury and anemia, we study Trypanosoma brucei and Trypanosoma congolense infections in C57BL/6 mice which associate with high and low tissue injury, respectively. In both models control of parasitemia involves the production of inflammatory mediators, including IFN??, TNF and NO, and the phagocytocis of antibody opsonized parasites by liver CD11b+ monocytic cells, especially liver resident macrophages or Kupffer cells. However, sustained and uncontrolled inflammation may lead to the development of tissue injury. Increased pathogenicity in the late stage of T. brucei infection correlates with maintained high levels of IFN?? production and activation of TNF/NO producing classically activated CD11b+ monocytic cells (M1) in the liver. In trypanotolerant T. congolense infected mice, control of liver injury in the late stage of infection associates with lower IFN?? production and reduced M1 activation on the one hand, and higher production of the anti?inflammatory cytokine IL?10 and the induction of alternatively activated CD11b+ monocytic cells (M2) on the other hand. To unravel the mechanisms involved in the induction of or protection from liver injury, we investigated i) the phenotype and functional role of different subsets of liver CD11b+ monocytic cells, ii) the role of IL?10 produced by CD11b+ monocytic cells as well as the downstream protective effects of IL?10 signaling during trypanosome infection, including the induction of M2 status in CD11b+ monocytic cells. Our results show that CD11b+Ly6C+ monocytic cells accumulate in the liver of trypanosome infected mice after their egression from the bone marrow in a CCL2/CCR2 dependent manner. CD11b+Ly6C+ monocytic cells differentiate in a two?step process involving MyD88 and IFN??R signaling towards so?called CD11b+Ly6C+CD11c+ TNF and iNOS producing Tip?DCs in the liver. Tip?DCs constitute an important liver M1 population in trypanosome infected mice as they produce TNF/NO and are involved in the activation of IFN?? producing Th1 cells. Moreover they play an important pathogenic role during infection since T. brucei infected CCR2 KO mice, which have drastically reduced numbers of Tip?DCs in the liver, have reduced liver pathogenicity and increased survival. In addition we have identified, characterized and isolated a CD11b+F4/80+Ly6C? subpopulation of liver monocytic cells from the liver of trypanosome infected mice. These cells have a highly activated, mature macrophage phenotype and display phagocytic capacity in vivo, resembling Kupffer?cell like cells. Kupffer?cell like cells from trypanosome infected mice produce TNF and upregulate the expression of inflammatory genes including T cell attracting/stimulatory molecules. However, they also express high levels of the il10 gene during infection suggesting they have the phenotype of a subset of immunoregulatory M2 monocytic cells, called M2b. The protective role of IL?10 during trypanosome infection was shown using anti?IL?10 receptor neutralizing antibodies, which drastically reduce the survival time of infected mice and increases the production of IFN??, TNF and NO in the liver. We show that IL?10 mediates this effect by blocking the differentiation of CD11b+Ly6C+ monocytic cells to pathogenic TNF/NO producing Tip?DCs. In addition, IL?10 limits the recruitment of pro?inflammatory cells to the liver, including CD11b+Ly6C+ monocytic cells by suppressing CCL2 production. In