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IRAK‐M regulates the inhibition of TLR‐mediated macrophage immune response during late in vitro Leishmania donovani infection

Intramacrophage protozoan parasite Leishmania donovani, causative agent of visceral leishmaniasis, escapes Toll‐like receptor (TLR) dependent early host immune response by inducing the deubiquitinating enzyme A20, which is sustained up to 6 h postinfection only. Therefore, Leishmania must apply other means to deactivate late host responses. Here, we elucidated the role of IL‐1 receptor‐associated kinase M (IRAK‐M), a negative regulator of TLR signaling, in downregulating macrophage proinflammatory response during late hours of in vitro infection. Our data reveal a sharp decline in IRAK1 and IRAK4 phosphorylation at 24 h postinfection along with markedly reduced association of IRAK1–TNF receptor associated factor 6, which is mandatory for TLR activation. In contrast, IRAK‐M was induced after A20 levels decreased and reached a maximum at 24 h postinfection. IRAK‐M induction coincided with increased stimulation of TGF‐β, a hallmark cytokine of visceral infection. TGF‐β‐dependent signaling‐mediated induction of SMAD family of proteins, 2, 3, and 4 plays important roles in transcriptional upregulation of IRAK‐M. In infected macrophages, siRNA‐mediated silencing of IRAK‐M displayed enhanced IRAK1 and IRAK4 phosphorylation with a concomitant increase in downstream NF‐κB activity and reduced parasite survival. Taken together, the results suggest that IRAK‐M may be targeted by L. donovani to inhibit TLR‐mediated proinflammatory response late during in vitro infection.