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


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Chandrakar, Pragya; Seth, Anuradha; Rani, Ankita; Dutta, Mukul; Parmar, Naveen; Descoteaux, Albert ORCID logoORCID: https://orcid.org/0000-0002-0633-5309 et Kar, Susanta (2021). Jagged/Notch-mediated divergence of immune cell crosstalk maintains anti-inflammatory response in visceral leishmaniasis Journal of Cell Science , vol. 134 , nº 5. pp. 1-13. DOI: 10.1242/jcs.252494.

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Notch signaling governs crucial aspects of intercellular communication spanning antigen-presenting cells and T-cells. In this study, we investigate how L. donovani takes advantage of this pathway to quell host immune responses. We report induction of Notch ligand, Jagged1 in L. donovani-infected bone marrow macrophages (BMMфs) and subsequent activation of RBPJκ in T cells, which in turn, upregulates transcription factor GATA3. Activated RBPJκ also associates with histone acetyltransferase, p300, which binds with Bcl2L12 promoter and enhances its expression. Interaction of Bcl2L12 with GATA3 in CD4(+) T cells facilitates its binding to IL-10 and IL-4 promoters, thereby increasing the secretion of these cytokines. Silencing Jagged1 hindered these events in a BMMф-T cell co-culture system. Upon further scrutiny, we found that parasite LPG induces the host PI3K/Akt pathway, which activates β-catenin and Egr1, the two transcription factors responsible for driving Jagged1 expression. Vivo 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 VL.

Type de document: Article
Mots-clés libres: Anti-Inflammatory Cytokines; Bone Marrow Macrophages; CD4+ T Cells; Jagged1–Notch Signaling; Leishmania Donovani
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 22 juin 2022 19:21
Dernière modification: 22 juin 2022 19:21
URI: https://espace.inrs.ca/id/eprint/12311

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