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

S Majumder, N Amatya, S Revu, CV Jawale, D Wu… - Nature …, 2019 - nature.com
S Majumder, N Amatya, S Revu, CV Jawale, D Wu, N Rittenhouse, A Menk, S Kupul, F Du…
Nature immunology, 2019nature.com
Lymph-node (LN) stromal cell populations expand during the inflammation that
accompanies T cell activation. Interleukin-17 (IL-17)-producing helper T cells (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 …
Abstract
Lymph-node (LN) stromal cell populations expand during the inflammation that accompanies T cell activation. Interleukin-17 (IL-17)-producing helper T cells (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 IκBζ 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.
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