Abstract
Ly6Chi inflammatory monocytes develop in the bone marrow and migrate to the site of infection during inflammation. Upon recruitment, Ly6Chi monocytes can differentiate into dendritic cells or macrophages. According to the tissue environment they can also acquire different functions. Several studies have described pre-activation of Ly6Chi monocytes in the bone marrow during parasitic infection, but whether this process occurs during experimental visceral leishmaniasis and, if so, the mechanisms contributing to their activation are yet to be established. In wild type C57BL/6 (B6) mice infected with Leishmania donovani, the number of bone marrow Ly6Chi monocytes increased over time. Ly6Chi monocytes displayed a highly activated phenotype from 28 days to 5 months post infection (p.i), with >90% expressing MHCII and >20% expressing iNOS. In comparison, in B6.Rag2 -/- mice <10% of bone marrow monocytes were MHCII+ at day 28 p.i., an activation deficiency that was reversed by adoptive transfer of CD4+ T cells. Depletion of CD4+ T cells in B6 mice and the use of mixed bone marrow chimeras further indicated that monocyte activation was driven by IFNγ produced by CD4+ T cells. In B6.Il10 -/- mice, L. donovani infection induced a faster but transient activation of bone marrow monocytes, which correlated with the magnitude of CD4+ T cell production of IFNγ and resolution of the infection. Under all of the above conditions, monocyte activation was associated with greater control of parasite load in the bone marrow. Through reinfection studies in B6.Il10 -/- mice and drug (AmBisome®) treatment of B6 mice, we also show the dependence of monocyte activation on parasite load. In summary, these data demonstrate that during L. donovani infection, Ly6Chi monocytes are primed in the bone marrow in a process driven by CD4+ T cells and whereby IFNγ promotes and IL-10 limits monocyte activation and that the presence of parasites/parasite antigen plays a crucial role in maintaining bone marrow monocyte activation.
Highlights
The bone marrow (BM) is the major site for hematopoiesis in adult mammals, producing all major cell lineages from a pool of committed precursors
In B6 mice, MHCII was abundant on almost all BM monocytes from d28 p.i. onwards whereas in B6.Rag2-/- mice, only 20% of monocytes expressed MHCII at later time points, with statistical difference reached at day 28, day 56 and day 152 (p
Our data extend a previous study of BM monocytes that demonstrated an elevation of MHCII expression on Ly6Chi Inflammatory monocytes (iMo) in the BM early during L. donovani infection [15] by conducting analysis into the chronic period of infection and though analysis of the mechanisms responsible for this finding
Summary
The bone marrow (BM) is the major site for hematopoiesis in adult mammals, producing all major cell lineages from a pool of committed precursors. Ly6Chi monocytes are highly plastic and depending on the environment, they can differentiate into a variety of cells including macrophages and dendritic cells (DCs) or maintain a monocyte phenotype [4, 5] It is unclear, whether such terminal differentiation only occurs once in the peripheral tissues or is initiated earlier during BM residency. Infection with Toxoplasma gondii led to the secretion of interferon-g (IFNg) by NK cells and this cytokine was responsible for monocyte priming and the development of regulatory capacity [7, 8] These and other studies [1, 6, 9, 10] collectively suggest that Ly6Chi monocytes may become functionally committed prior to their arrival at sites of tissue inflammation or infection
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