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  • Jagged-Notch-mediated divergence of immune cell crosstalk maintains the anti-inflammatory response in visceral leishmaniasis.

Jagged-Notch-mediated divergence of immune cell crosstalk maintains the anti-inflammatory response in visceral leishmaniasis.

Journal of cell science (2021-02-17)
Pragya Chandrakar, Anuradha Seth, Ankita Rani, Mukul Dutta, Naveen Parmar, Albert Descoteaux, Susanta Kar
ABSTRACT

Notch signaling governs crucial aspects of intercellular communication spanning antigen-presenting cells and T-cells. In this study, we investigate how Leishmania donovani takes advantage of this pathway to quell host immune responses. We report induction of the Notch ligand Jagged1 in L. donovani-infected bone marrow macrophages (BMMϕs) and subsequent activation of RBPJκ (also known as RBPJ) in T cells, which in turn upregulates the transcription factor GATA3. Activated RBPJκ also associates with the histone acetyltransferase p300 (also known as EP300), which binds with the Bcl2l12 promoter and enhances its expression. Interaction of Bcl2L12 with GATA3 in CD4+ T cells facilitates its binding to the interleukin (IL)-10 and IL-4 promoters, thereby increasing the secretion of these cytokines. Silencing Jagged1 hindered these events in a BMMϕ-T cell co-culture system. Upon further scrutiny, we found that parasite lipophosphoglycan (LPG) induces the host phosphoinositide 3-kinase (PI3K)/Akt pathway, which activates β-catenin and Egr1, the two transcription factors responsible for driving Jagged1 expression. In v ivo morpholino-silencing of Jagged1 suppresses anti-inflammatory cytokine responses and reduces organ parasite burden in L. donovani-infected Balb/c mice, suggesting that L. donovani-induced host Jagged1-Notch signaling skews macrophage-T cell crosstalk into disease-promoting Th2 mode in experimental visceral leishmaniasis.This article has an associated First Person interview with the first author of the paper.

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Protease Inhibitor Cocktail, for use with mammalian cell and tissue extracts, DMSO solution
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Anti-RBPJ Antibody, serum, from rabbit
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