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

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Title IRAK-M regulates the inhibition of TLR-mediated
macrophage immune response during late in vitro
Leishmania donovani infection
 
Creator Srivastav, Supriya
Saha, Amrita
Barua, Jayita
Ukil, Anindita
Das, Pijush K
 
Subject Infectious Diseases and Immunology
 
Description 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 kinaseM(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
 
Publisher John Wiley & Sons
 
Date 2015
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2350/1/EUROPEAN_JOURNAL_OF_IMMUNOLOGY__V_45_(__10_)_2787%2D2797_;2015.pdf
Srivastav, Supriya and Saha, Amrita and Barua, Jayita and Ukil, Anindita and Das, Pijush K (2015) IRAK-M regulates the inhibition of TLR-mediated macrophage immune response during late in vitro Leishmania donovani infection. European Journal of Immunology, 45 (10). pp. 2787-2797. ISSN 0014-2980
 
Relation http://dx.doi.org/10.1002/eji.201445336
http://www.eprints.iicb.res.in/2350/