Dataset Information

Obesity-induced dysregulation of skin-resident PPARγ⁺ Treg cells promotes IL-17A-mediated psoriatic inflammation.

ABSTRACT: Obesity is a major risk factor for psoriasis, but how obesity disrupts the regulatory mechanisms that keep skin inflammation in check is unclear. Here, we found that skin was enriched with a unique population of CD4⁺Foxp3⁺ regulatory T (Treg) cells expressing the nuclear receptor peroxisome proliferation-activated receptor gamma (PPARγ). PPARγ drove a distinctive transcriptional program and functional suppression of IL-17A⁺ γδ T cell-mediated psoriatic inflammation. Diet-induced obesity, however, resulted in a reduction of PPARγ⁺ skin Treg cells and a corresponding loss of control over IL-17A⁺ γδ T cell-mediated inflammation. Mechanistically, PPARγ⁺ skin Treg cells preferentially took up elevated levels of long-chain free fatty acids in obese mice, which led to cellular lipotoxicity, oxidative stress, and mitochondrial dysfunction. Harnessing the anti-inflammatory properties of these PPARγ⁺ skin Treg cells could have therapeutic potential for obesity-associated inflammatory skin diseases.

SUBMITTER: Sivasami P

PROVIDER: S-EPMC10527179 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation.

Sivasami Pulavendran P Elkins Cody C Diaz-Saldana Pamela P PP Goss Kyndal K Peng Amy A Hamersky Michael M Bae Jennifer J Xu Miaoer M Pollack Brian P BP Horwitz Edwin M EM Scharer Christopher D CD Seldin Lindsey L Li Chaoran C

Immunity 20230720 8

Obesity is a major risk factor for psoriasis, but how obesity disrupts the regulatory mechanisms that keep skin inflammation in check is unclear. Here, we found that skin was enriched with a unique population of CD4+Foxp3+ regulatory T (Treg) cells expressing the nuclear receptor peroxisome proliferation-activated receptor gamma (PPARγ). PPARγ drove a distinctive transcriptional program and functional suppression of IL-17A+ γδ T cell-mediated psoriatic inflammati ...[more]

PMID: 37478855

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Project description:The importance and exact role of graft-resident leucocytes (also referred to as passenger leucocytes) in transplantation is controversial as these cells have been reported to either initiate or retard graft rejection. T cell activation to allografts is mediated via recognition of intact or processed donor MHC molecules on antigen-presenting cells (APC) as well as through interaction with donor-derived extracellular vesicles. Reduction of graft-resident leucocytes before transplantation is a well-known approach for prolonging organ survival without interfering with the recipient's immune system. As previously shown by our group, injecting mice with IL-2/anti-IL-2 complexes (IL-2cplx) to augment expansion of CD4 T regulatory cells (Tregs) induces tolerance towards islet allografts, and also to skin allografts when IL-2cplx treatment is supplemented with rapamycin and a short-term treatment of anti-IL-6. In this study, we investigated the mechanisms by which graft-resident leucocytes impact graft survival by studying the combined effects of IL-2cplx-mediated Treg expansion and passenger leucocyte depletion. For the latter, effective depletion of APC and T cells within the graft was induced by prior total body irradiation (TBI) of the graft donor. Surprisingly, substantial depletion of donor-derived leucocytes by TBI did not prolong graft survival in naïve mice, although it did result in augmented recipient leucocyte graft infiltration, presumably through irradiation-induced nonspecific inflammation. Notably, treatment with the IL-2cplx protocol prevented early inflammation of irradiated grafts, which correlated with an influx of Tregs into the grafts. This finding suggested there might be a synergistic effect of Treg expansion and graft-resident leucocyte depletion. In support of this idea, significant prolongation of skin graft survival was achieved if we combined graft-resident leucocyte depletion with the IL-2cplx protocol; this finding correlated along with a progressive shift in the composition of T cells subsets in the grafts towards a more tolerogenic environment. Donor-specific humoral responses remained unchanged, indicating minor importance of graft-resident leucocytes in anti-donor antibody development. These results demonstrate the importance of donor-derived leucocytes as well as Tregs in allograft survival, which might give rise to new clinical approaches.

Dataset Information

Obesity-induced dysregulation of skin-resident PPARγ⁺ Treg cells promotes IL-17A-mediated psoriatic inflammation.

Publications

Obesity-induced dysregulation of skin-resident PPARγ<sup>+</sup> Treg cells promotes IL-17A-mediated psoriatic inflammation.

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