Hepatocyte-derived IL-10 plays a crucial role in attenuating pathogenicity during the chronic phase of T. congolense infection

Abstract

Bovine African Trypanosomosis is an infectious parasitic disease affecting livestock productivity and thereby impairing the economic development of Sub-Saharan Africa. The most important trypanosome species implicated is T. congolense, causing anemia as most important pathological feature. Using murine models, it was shown that due to the parasite's efficient immune evasion mechanisms, including (i) antigenic variation of the variable surface glycoprotein (VSG) coat, (ii) induction of polyclonal B cell activation, (iii) loss of B cell memory and (iv) T cell mediated immunosuppression, disease prevention through vaccination has so far been impossible. In trypanotolerant models a strong, early pro-inflammatory immune response involving IFN-γ, TNF and NO, combined with a strong humoral anti-VSG response, ensures early parasitemia control. This potent protective inflammatory response is counterbalanced by the production of the anti-inflammatory cytokine IL-10, which in turn prevents early death of the host from uncontrolled hyper-inflammation-mediated immunopathologies. Though at this stage different hematopoietic cells, such as NK cells, T cells and B cells as well as myeloid cells (i.e. alternatively activated myeloid cells (M2) or Ly6cmonocytes), were found to produce IL-10, the contribution of non-hematopoietic cells as potential IL-10 source during experimental T. congolense infection has not been addressed. Here, we report for the first time that during the chronic stage of T. congolense infection nonhematopoietic cells constitute an important source of IL-10. Our data shows that hepatocyte-derived IL-10 is mandatory for host survival and is crucial for the control of trypanosomosis-induced inflammation and associated immunopathologies such as anemia, hepatosplenomegaly and excessive tissue injury.

The Role of MIF and IL-10 as Molecular Yin-Yang in the Modulation of the Host Immune Microenvironment During Infections: African Trypanosome Infections as a Paradigm

“…Examples include the Foxp3 and B lymphocyte-induced maturation protein-1 (Blimp-1) factors for both regulatory and effector type I regulatory (Tr1) T cells, respectively as well as the IL-27 cytokine for CD4 + and CD8 + effector T cells ( 166 – 170 ). Next to immune cells, IL-10 can also be produced by several non-immune cells such as hepatocytes and keratinocytes ( 48 , 171 , 172 ).…”

“…As mentioned earlier, infection with African trypanosomes is associated with the development of a strong early pro-inflammatory immune response that culminates into severe immunopathologies and death if not tightly controlled. The IL-10 cytokine, with its anti-inflammatory character, was already shown to play a crucial role in counterbalancing this strong pro-inflammatory environment, thereby limiting pathology, but, in contrast, does not seem to modulate African trypanosome parasite control ( 42 , 45 , 48 , 189 – 192 ). For example, IL-10 can dampen the differentiation of monocytes to Tip-DCs (TNF/iNOS-producing DCs) that have been shown to contribute to tissue damage during the chronic stage of T. b. brucei infection, i.e.…”

“…During T. congolense infection, i.e. Tc13 model, which is associated with a stronger and more sustained IL-10 production ( 48 , 50 , 192 ), additional leukocyte types have been found to produce IL-10. Indeed, both naturally occurring CD4 + Foxp3 + Tregs as well as different myeloid cell subsets, including Ly6C - patrolling monocytes and alternatively activated macrophages, were shown to constitute sources of IL-10 during the early stages of infection ( 49 – 51 , 192 , 195 ).…”

“…Particularly, the production of IL-10 was shown to be crucial to prevent the development of an uncontrolled inflammation syndrome, associated with early mortality ( 42 , 45 ). Depending on the trypanosome species and the stage of infection, different cellular sources could contribute to IL-10 production such as NK cells, CD8 + T cells and CD4 + T cells around peak parasitaemia as well as B cells and plasma cells, myeloid cells and hepatocytes as the infection progresses ( 45 , 48 – 51 ). Furthermore, the level of IL-10 induction might also differ between different mouse strains ( 52 ).…”

“…Strategies that either promote IL-10 production (i.e. AAV-IL-10 or anti-CD28 treatment) or block MIF (such as antibodies or small molecules) establish a new balance that prevents tissue injury ( 42 , 48 , 58 , 59 ).…”