IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival.
Saikat MajumderNilesh AmatyaShankar RevuChetan V JawaleDongwen WuNatalie RittenhouseAshley MenkSaran KupulFang DuItay RaphaelAmrita BhattacharjeeUlrich SiebenlistTimothy W HandGreg M DelgoffeAmanda C PoholekSarah L GaffenPartha S BiswasMandy J McGeachyPublished in: Nature immunology (2019)
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.
Keyphrases
- cell cycle arrest
- induced apoptosis
- cell death
- pi k akt
- signaling pathway
- oxidative stress
- lymph node
- endoplasmic reticulum stress
- fatty acid
- stem cells
- magnetic resonance imaging
- metabolic syndrome
- poor prognosis
- early stage
- single cell
- type diabetes
- bone marrow
- insulin resistance
- squamous cell carcinoma
- gene expression
- binding protein
- dna methylation
- skeletal muscle
- heat shock
- magnetic resonance
- blood glucose
- genome wide
- nitric oxide
- hydrogen peroxide
- regulatory t cells
- inflammatory response
- visible light
- neoadjuvant chemotherapy
- heat stress