Role of TNF in the regulation of the innate immune response in Leishmaniasis

The absence of tumor necrosis factor (TNF) causes lethal infection by Leishmania major (L. major) in normally resistant mice C57BL/6J (B6.WT) mice, but the underlying mechanism has so far remained elusive. We found B6.WT mice without the TNF gene (B6.TNF-/-) displayed not only non-healing cutaneous lesions but also serious liver and spleen infection upon L. major infection. The enlarged liver showed increased inflammation and harbored a new monocyte- derived-macrophage population showing a CD45\\(^+\\)F4/80\\(^+\\)Ly6C\\(^{low}\\)CD11b\\(^{hi}\\) phenotype. This population continuously accumulated and typically displayed a M2 macrophage phenotype with high expression of CD206, Arginase-1 and interleukin-6 (IL-6). Of note, IL-6 is normally considered as a pro-inflammatory cytokine, but it also has been shown to have anti- inflammatory properties. Absence of TNF induced increased IL-6 expression and upregulated M-CSF receptor expression downstream. The elevated IL-6 level skewed monocyte differentiation from dendritic cells (DCs) to macrophages. Furthermore, TNF inhibited both IL-6-induced gp130-STAT3 and IL-4-STAT6 signaling activation, thereby abrogating an IL- 6 facilitated M2 macrophage polarization. Spleens from B6.TNF-/- mice were around three times larger than B6.WT mice and contained significantly more parasites. Plasmacytoid dendritic cells (pDC) are the key immune inducing population during leishmaniasis, producing IL-12 and promoting a Th1 immune response. B6.TNF\\(^{-/-}\\) mice displayed significantly fewer pDC and a non-defined B220\\(^+\\) monocyte-derived cell population compared to B6.WT mice. T cells and B cells did not show significant differences between the two strains, but CD11b\\(^+\\)F4/80\\(^+\\) cells were found to be in higher numbers in B6.TNF\\(^{-/-}\\) mice. Therefore, our results set the basis to investigate the role of IL-6 signaling in macrophage polarization. Our findings also demonstrated the critical role of TNF in the development of different DC populations, that may subsequently affect T cell-mediated protection against L. major infection. In conclusion, these findings may potentially explain the increased risk of opportunistic infection and relapses in patients receiving anti-TNF treatment.