TY - JOUR
T1 - Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell–Associated Pathogenicity in Chronic Intestinal Inflammation
AU - Bamidele, Adebowale O.
AU - Mishra, Shravan K.
AU - Piovezani Ramos, Guilherme
AU - Hirsova, Petra
AU - Klatt, Emily E.
AU - Abdelrahman, Leena M.
AU - Sagstetter, Mary R.
AU - Davidson, Heidi M.
AU - Fehrenbach, Patrick J.
AU - Valenzuela-Pérez, Lucía
AU - Kim Lee, Hyun Se
AU - Zhang, Song
AU - Aguirre Lopez, Abner
AU - Kurdi, Ahmed T.
AU - Westphal, Maria S.
AU - Gonzalez, Michelle M.
AU - Gaballa, Joseph M.
AU - Kosinsky, Robyn Laura
AU - Lee, Hee Eun
AU - Smyrk, Thomas C.
AU - Bantug, Glenn
AU - Gades, Naomi M.
AU - Faubion, William A.
N1 - Publisher Copyright:
© 2024 AGA Institute
PY - 2024
Y1 - 2024
N2 - Background & Aims: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. Methods: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell–induced murine colitis models. Results: Mitochondria–endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria–endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 β pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r–/– Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. Conclusions: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell–driven chronic intestinal inflammation.
AB - Background & Aims: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. Methods: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell–induced murine colitis models. Results: Mitochondria–endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria–endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 β pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r–/– Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. Conclusions: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell–driven chronic intestinal inflammation.
KW - Inflammatory Bowel Disease
KW - Interleukins
KW - Mitochondria-ER Appositions
KW - Pyruvate
KW - Regulatory T Cells
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UR - http://www.scopus.com/inward/citedby.url?scp=85187451637&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2024.01.026
DO - 10.1053/j.gastro.2024.01.026
M3 - Article
C2 - 38266738
AN - SCOPUS:85187451637
SN - 0016-5085
VL - 166
SP - 826-841.e19
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -