NCoR1 and SMRT fine-tune inflammatory versus tolerogenic balance in dendritic cells by differentially regulating STAT3 signaling

Raghav, S. K.; Jha, A.; Ahad, A.; Mishra, G. P.; Sen, K.; Smita, S.; Minz, A. P.; Biswas, V. K.; Tripathy, A.; Senapati, S. B.; Gupta, B.; Orbea, H. A.

doi:10.1101/2021.03.11.434976

bioRxiv · 10.1101/2021.03.11.434976

NCoR1 and SMRT fine-tune inflammatory versus tolerogenic balance in dendritic cells by differentially regulating STAT3 signaling

Raghav, S. K.·Jha, A.·Ahad, A.·Mishra, G. P.·Sen, K.·Smita, S.·Minz, A. P.·Biswas, V. K.·Tripathy, A.·Senapati, S. B.·Gupta, B.·Orbea, H. A.

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Abstract

Dendritic cell (DC) fine-tunes inflammatory versus tolerogenic responses to protect from immune-pathology. However, the role of co-regulators in maintaining this balance is unexplored. NCoR1-mediated repression of DC immune-tolerance has been recently reported. Here we found that depletion of NCoR1 paralog SMRT (NCoR2) enhanced cDC1 activation and expression of IL-6, IL-12 and IL-23 while concomitantly decreasing IL-10 expression/secretion. Consequently, co-cultured CD4+ and CD8+ T-cells depicted enhanced Th1/Th17 frequency and cytotoxicity, respectively. Comparative genomic and transcriptomic analysis demonstrated differential regulation of IL-10 by SMRT and NCoR1. SMRT depletion represses mTOR-STAT3-IL10 signaling in cDC1 by downregulating NR4A1. Besides, Nfkbia and Socs3 were down-regulated in Ncor2 (Smrt) knockdown cDC1, supporting increased production of inflammatory cytokines. Moreover, studies in mice showed, adoptive transfer of SMRT knockdown cDC1 in OVA-DTH induced footpad inflammation led to increased Th1/Th17 and reduced tumor burden after B16 melanoma injection by enhancing oncolytic CD8+ T-cell frequency, respectively. We also depicted decreased Ncor2 expression in Rheumatoid Arthritis, a Th1/Th17 disease.

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Raghav, S. K., Jha, A., Ahad, A., Mishra, G. P., Sen, K., Smita, S., Minz, A. P., Biswas, V. K., Tripathy, A., Senapati, S. B., Gupta, B., Orbea, H. A.. 2021-03-12. NCoR1 and SMRT fine-tune inflammatory versus tolerogenic balance in dendritic cells by differentially regulating STAT3 signaling. https://doi.org/10.1101/2021.03.11.434976

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