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