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Differential Induction of SOCS Isoforms by Leishmania donovani Impairs Macrophage-T Cell Cross-Talk and Host Defense

Chandrakar, Pragya, Parmar, Naveen, Descoteaux, Albert ORCID: https://orcid.org/0000-0002-0633-5309 et Kar, Susanta (2020). Differential Induction of SOCS Isoforms by Leishmania donovani Impairs Macrophage-T Cell Cross-Talk and Host Defense Journal of Immunology , vol. 204 , nº 3. p. 596-610. DOI: 10.4049/jimmunol.1900412.

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Résumé

Immune evasion strategies adopted by Leishmania donovani involve the exploitation of suppressor of cytokine signaling (SOCS) proteins that are well-known negative regulators of the JAK/STAT pathway. However, the cellular mechanism underpinning the induction of SOCS isoforms and their role in breaching the multilevel regulatory circuit connecting the innate and adaptive arms of immunity are still ambiguous during experimental visceral leishmaniasis. Using bone marrow-derived macrophages (BMMsmall ef, Cyrillics) and CD4(+) T cells, we observed that L. donovani preferentially upregulates SOCS1 and SOCS3 expression in macrophages and T cells, respectively, whereas the SOCS1 level remains consistently high in BMMsmall ef, Cyrillics and SOCS3 expression is pronounced and long lasting in T cells. Consequently, this inhibits STAT1-mediated IL-12 induction in macrophages and STAT4-mediated IFN-gamma synthesis in T cells. Mechanistically, PI3K/Akt-mediated SRF activation promotes nuclear translocation and binding of Egr2 to SOCS1 promoter for its early induction in infected BMMsmall ef, Cyrillics. Additionally, L. donovani activates IDO/kynurenine/AHR signaling in BMMsmall ef, Cyrillics to maintain prolonged SOCS1 expression. Later, PGE2, secreted from infected BMMsmall ef, Cyrillics induces cAMP-PKA pathway by binding to the EP2/EP4 receptor of CD4(+) T cells, leading to SP1, CREB, and GATA1 activation and SOCS3 expression. Small interfering RNA-mediated silencing of SOCS1 and SOCS3 in macrophage and T cells, respectively, restored IL-12 and IFN-gamma cytokine levels and BMMsmall ef, Cyrillic-T cell interaction. Vivo morpholino-mediated silencing of SOCS1 and SOCS3 resulted in protective cytokine responses, thereby reducing organ parasite burden significantly in L. donovani-infected BALB/c mice. Collectively, our results imply that L. donovani orchestrates different SOCS isoforms to impair macrophage-T cell cross-talk and preserve its own niche.

Type de document: Article
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Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 22 juill. 2021 21:57
Dernière modification: 07 févr. 2022 13:56
URI: https://espace.inrs.ca/id/eprint/11558

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