TNF deficiency leads to splenomegaly during Cutaneous Leishmaniasis

Abstract

Abstract Cutaneous leishmaniasis in resistant C57BL/6 (B6.WT) mice is resolved spontaneously by Th-1 mediated production of TNF-α and IFN-γ, with consequent induction of inducible nitric oxide synthase. Intriguingly, C57BL/6 mice with a TNF gene knockout (B6.TNF−/−) show uncontrolled fatal infection involving the liver and spleen, which are the two main targets in visceral leishmaniasis. The exact role of TNF or specific mechanism, which is responsible for the fatal outcome of Leishmania infection in this gene-deficient mouse strain, is not yet understood. B6.TNF−/− mice spleen significantly enlarged from Day 28 post-infection, and they were more than 2-fold larger than B6.WT mice on Day 35 and Day 42. To confirm Leishmania infection in the spleen, limiting dilution assay was recruited and showed Leishmania existed since Day 21 in B6.TNF−/− mice, but there was none evident in B6.WT mice. Diff Quik stain results confirmed that architecture of spleen in B6.TNF−/− was disorganized and white and red pulps were no longer clearly separated. Cells infected with Leishmania were dispersed throughout the spleen and lymph cells infiltrated. A gradually increasing population CD45+CD11b+CD11chighCCR2+Ly6C+F4/80high was emerged in B6.TNF−/− mice, which had both dendritic cell and macrophages like phenotype. In vitro, at steady state, macrophages from B6.TNF−/− mice showed no difference comparing to B6.WT. After exposure with Leishmania promastigotes, they showed potential M2-like phenotype and more easily succumbed to infection We are currently sorting this population from B6.TNF−/− mice and examining the characteristics and potential mechanisms that may affect the spleen immunity against Leishmania major infection in the absence of TNF.