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

Abstract

Notch signaling governs crucial aspects of intercellular communication spanning antigen-presenting cells and T-cells. In this study, we investigate how <i>Leishmania</i><i>donovani</i> takes advantage of this pathway to quell host immune responses. We report induction of the Notch ligand Jagged1 in <i>L. donovani</i>-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 <i>Bcl2l12</i> 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. <i>In v</i><i>ivo</i> morpholino-silencing of Jagged1 suppresses anti-inflammatory cytokine responses and reduces organ parasite burden in <i>L. donovani</i>-infected Balb/c mice, suggesting that <i>L. donovani</i>-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.