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IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival

Majumder, S;Amatya, N;Revu, S;Jawale, CV;Wu, D;Rittenhouse, N;Menk, A;Kupul, S;Du, F;Raphael, I;Bhattacharjee, A;Siebenlist, U;Hand, TW;Delgoffe, GM;Poholek, AC;Gaffen, SL;Biswas, PS;McGeachy, MJ;

Lymph-node (LN) stromal cell populations expand during the inflammation that accompanies Tcell activation. Interleukin-17 (IL-17)-producing helper Tcells (TH17 cells) promote inflammation through the induction of cytokines and chemokines in peripheral tissues. We demonstrate a critical requirement for IL-17 in the proliferation of LN and splenic stromal cells, particularly fibroblastic reticular cells (FRCs), during experimental autoimmune encephalomyelitis and colitis. Without signaling via the IL-17 receptor, activated FRCs underwent cell cycle arrest and apoptosis, accompanied by signs of nutrient stress in vivo. IL-17 signaling in FRCs was not required for the development of TH17 cells, but failed FRC proliferation impaired germinal center formation and antigen-specific antibody production. Induction of the transcriptional co-activator IB via IL-17 signaling mediated increased glucose uptake and expression of the gene Cpt1a, encoding CPT1A, a rate-limiting enzyme of mitochondrial fatty acid oxidation. Hence, IL-17 produced by locally differentiating TH17 cells is an important driver of the activation of inflamed LN stromal cells, through metabolic reprogramming required to support proliferation and survival.