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Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell–Associated Pathogenicity in Chronic Intestinal Inflammation

Bamidele, Adebowale O. ; Mishra, Shravan K. ; Piovezani Ramos, Guilherme ; Hirsova, Petra ; Klatt, Emily E. ; Abdelrahman, Leena M. ; Sagstetter, Mary R. ; Davidson, Heidi M. ; Fehrenbach, Patrick J. ; Valenzuela-Pérez, Lucía ; Kim Lee, Hyun Se ; Zhang, Song ; Aguirre Lopez, Abner ; Kurdi, Ahmed T. ; Westphal, Maria S. ; Gonzalez, Michelle M. ; Gaballa, Joseph M. ; Kosinsky, Robyn Laura ; Lee, Hee Eun ; Smyrk, Thomas C. ; Bantug, Glenn ; Gades, Naomi M. ; Faubion, William A.

Gastroenterology (New York, N.Y. 1943), 2024-05, Vol.166 (5), p.826-841.e19 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell–Associated Pathogenicity in Chronic Intestinal Inflammation
Autor: Bamidele, Adebowale O. ; Mishra, Shravan K. ; Piovezani Ramos, Guilherme ; Hirsova, Petra ; Klatt, Emily E. ; Abdelrahman, Leena M. ; Sagstetter, Mary R. ; Davidson, Heidi M. ; Fehrenbach, Patrick J. ; Valenzuela-Pérez, Lucía ; Kim Lee, Hyun Se ; Zhang, Song ; Aguirre Lopez, Abner ; Kurdi, Ahmed T. ; Westphal, Maria S. ; Gonzalez, Michelle M. ; Gaballa, Joseph M. ; Kosinsky, Robyn Laura ; Lee, Hee Eun ; Smyrk, Thomas C. ; Bantug, Glenn ; Gades, Naomi M. ; Faubion, William A.
Assuntos: Animals ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; Chronic Disease ; Colitis - immunology ; Colitis - metabolism ; Colitis - pathology ; Crohn Disease - immunology ; Crohn Disease - metabolism ; Crohn Disease - pathology ; Humans ; Inflammatory Bowel Disease ; Interleukins ; Interleukins - metabolism ; Interleukins - pharmacology ; Mice ; Mice, Inbred C57BL ; Mitochondria - metabolism ; Mitochondria-ER Appositions ; Pyruvate ; Regulatory T Cells ; T-Lymphocytes, Regulatory - immunology ; Voltage-Dependent Anion Channel 1 - genetics ; Voltage-Dependent Anion Channel 1 - metabolism
É parte de: Gastroenterology (New York, N.Y. 1943), 2024-05, Vol.166 (5), p.826-841.e19
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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. 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. 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. IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell–driven chronic intestinal inflammation. [Display omitted] Interleukin 21 induces metabolic alterations and acquisition of an inflammatory-like phenotype by perturbing mitochondria–endoplasmic reticulum crosstalk, thereby diminishing the capacity of Tregs in suppressing inflammatory bowel disease.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell–Associated Pathogenicity in Chronic Intestinal Inflammation

United States: Elsevier Inc

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