Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells

Jacobse, Justin; Brown, Rachel E.; Li, Jing; Pilat, Jennifer M.; Pham, Ly; Short, Sarah P.; Peek, Christopher T.; Rolong, Andrea; Washington, Mary Kay; Martı́nez-Barricarte, Rubén; Byndloss, Mariana X.; Shelton, Catherine; Markle, Janet; Latour, Yvonne L.; Allaman, Margaret M.; Cassat, James E.; Wilson, Keith T.; Choksi, Yash A.; Williams, Christopher S.; Lau, Ken S.; Flynn, Charles R.; Casanova, Jean‐Laurent; Rings, E. H. H. M.; Samsom, Janneke N.; Goettel, Jeremy A.

doi:10.1016/j.celrep.2023.112128

Cited by 19 publications

(21 citation statements)

References 85 publications

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“…Additionally, Hcy also promotes the expression of IL-23R on the surface of Th17 cells. IL-23R serves as a crucial surface marker for Th17 cells, as it plays a signi cant role in maintaining the Th17 phenotype and facilitating Th17 proliferation via IL-23R [31] .…”

Section: Discussionmentioning

confidence: 99%

Homocysteine Promotes Intestinal Inflammation in Colitis Mice Through the PGE2/STAT3 Signaling Pathway

Shao,

Zhao,

Chen

2024

Preprint

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Background Our previous study indicated that Hcy exacerbated DSS-induced colitis by facilitating the differentiation of intestinal T helper cell 17 (Th17), but the precise mechanism remains unidentified. Therefore, our current research aims to elucidate the signaling pathway through which Hcy promotes the differentiation of Th17 cells. Methods BALb/c mice were randomly assigned into six groups. The model of mice colitis was induced using 3% DSS, while the model of Hyperhomocysteinaemia was induced using 1.7% methionine. The concentrations of Hcy and prostaglandin E2 (PGE2) were measured using enzyme linked immunosorbent assay (ELISA). The protein expressions of cytosolic phospholipase A2 (cPLA2), phosphorylated-cPLA2 (p-cPLA2), cyclooxygenase 2 (COX2), cyclic adenosine monophosphate (cAMP), signal transducer and activator of transcription 3 (STAT3), phosphorylated-STAT3 (p-STAT3), interleukin 17A (IL-17A) and retinoid-related orphan nuclear receptor-γt (RORγt) were assessed using western blot analysis. Results Compared to the DSS+HHcy group, the addition of the COX inhibitor did not significantly alter the protein expression of p-PLA2/PLA2, but led to significant decreases in serum PGE2 concentration, cAMP and p-STAT3/STAT3 protein expression. The protein expressions of p-PLA2/PLA2, COX2, and cAMP upstream of STAT3 inhibitor addition did not exhibit significant changes. However, PGE2 concentration and p-STAT3/STAT3 protein expression were notably reduced. After the COX inhibitor and STAT3 inhibitor added, the protein expression of IL-17A and RORγt and the levels of IL-17A and IL-23R in CD4+T cells were significantly reduced. Conclusion HHcy aggravated DSS-induced colitis by promoting the differentiation and proliferation of Th17 cells through the PGE2 / STAT3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Homocysteine Promotes Intestinal Inflammation in Colitis Mice Through the PGE2/STAT3 Signaling Pathway

Shao,

Zhao,

Chen

2024

Preprint

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“…Murine intestinal Treg express higher levels of Il23r than Treg in other tissues [52], and expression of RORγt and IL-23R depends on the microbiota strain [53,54]. In a colitis model, IL-23R signaling decreases Treg frequency in the gut and impairs their suppressive functions [52,55], possibly because of reduced expression of Foxp3 [56]. However, Yang et al [51] described the enhanced suppressive activity of the Foxp3 + RORγt + T-cell population in a colitis model, a difference that may depend on the different donor strains used for the transfer.…”

Section: Il-23r In Conventional T Cellsmentioning

confidence: 94%

“…A subset of regulatory T cells that expresses the transcription factor RORγt may also be responsive to IL‐23 [51], although IL‐23 signaling in this population may have different outcomes in different experimental settings, suggesting the need for further investigation. Murine intestinal Treg express higher levels of Il23r than Treg in other tissues [52], and expression of RORγt and IL‐23R depends on the microbiota strain [53, 54]. In a colitis model, IL‐23R signaling decreases Treg frequency in the gut and impairs their suppressive functions [52, 55], possibly because of reduced expression of Foxp3 [56].…”

Section: Introductionmentioning

confidence: 99%

Interleukin 23 receptor: Expression and regulation in immune cells

Mezghiche,

Yahia‐Cherbal,

Rogge

et al. 2023

Eur J Immunol

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“…In fact, these cells possess intrinsic mechanisms to avoid their full conversion towards T H 17 cells. As with IL-12 and T H 1 cells, subsequent signals provided by IL-23(Stat3) can further destabilise the transcriptional program of RORγT + T REG cells and even engage an apoptotic cascade in these cells ( 245 ). Indeed, Il23r is amongst the genes upregulated by Stat3 and RORγT ( 246 ), making RORγT + eT REG particularly sensitive to IL-23 ( 245 ).…”

Section: The Inflammatory Adaptation Of Tr-t Regmentioning

confidence: 99%

Deciphering the developmental trajectory of tissue-resident Foxp3+ regulatory T cells

Alvarez,

Liu,

Bay

et al. 2024

Front. Immunol.

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Foxp3+ TREG cells have been at the focus of intense investigation for their recognized roles in preventing autoimmunity, facilitating tissue recuperation following injury, and orchestrating a tolerance to innocuous non-self-antigens. To perform these critical tasks, TREG cells undergo deep epigenetic, transcriptional, and post-transcriptional changes that allow them to adapt to conditions found in tissues both at steady-state and during inflammation. The path leading TREG cells to express these tissue-specialized phenotypes begins during thymic development, and is further driven by epigenetic and transcriptional modifications following TCR engagement and polarizing signals in the periphery. However, this process is highly regulated and requires TREG cells to adopt strategies to avoid losing their regulatory program altogether. Here, we review the origins of tissue-resident TREG cells, from their thymic and peripheral development to the transcriptional regulators involved in their tissue residency program. In addition, we discuss the distinct signalling pathways that engage the inflammatory adaptation of tissue-resident TREG cells, and how they relate to their ability to recognize tissue and pathogen-derived danger signals.

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Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells

Cited by 19 publications

References 85 publications

Homocysteine Promotes Intestinal Inflammation in Colitis Mice Through the PGE2/STAT3 Signaling Pathway

Homocysteine Promotes Intestinal Inflammation in Colitis Mice Through the PGE2/STAT3 Signaling Pathway

Interleukin 23 receptor: Expression and regulation in immune cells

Deciphering the developmental trajectory of tissue-resident Foxp3+ regulatory T cells

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