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ROR?-expressing T regulatory cells restrain allergic skin inflammation.

ABSTRACT: Atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s) and T helper 2 (TH2) cells, and tissue eosinophilia. Using two distinct mouse models of atopic dermatitis, we show that expression of retinoid-related orphan receptor ? (ROR?) in skin-resident T regulatory cells (Tregs) is important for restraining allergic skin inflammation. In both models, targeted deletion of ROR? in mouse Tregs led to exaggerated eosinophilia driven by interleukin-5 (IL-5) production by ILC2s and TH2 cells. Expression of ROR? in skin-resident Tregs suppressed IL-4 expression and enhanced expression of death receptor 3 (DR3), which is the receptor for tumor necrosis factor (TNF) family cytokine, TNF ligand-related molecule 1 (TL1A), which promotes Treg functions. DR3 is expressed on both ILC2s and skin-resident Tregs Upon deletion of ROR? in skin-resident Tregs, we found that Tregs were no longer able to sequester TL1A, resulting in enhanced ILC2 activation. We also documented higher expression of ROR? in skin-resident Tregs than in peripheral blood circulating Tregs in humans, suggesting that ROR? and the TL1A-DR3 circuit could be therapeutically targeted in atopic dermatitis.

SUBMITTER: Malhotra N

PROVIDER: S-EPMC5912895 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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RORα-expressing T regulatory cells restrain allergic skin inflammation.

Malhotra Nidhi N Leyva-Castillo Juan Manuel JM Jadhav Unmesh U Barreiro Olga O Kam Christy C O'Neill Nicholas K NK Meylan Francoise F Chambon Pierre P von Andrian Ulrich H UH Siegel Richard M RM Wang Eddie C EC Shivdasani Ramesh R Geha Raif S RS

Science immunology 20180301 21

Atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s) and T helper 2 (T<sub>H</sub>2) cells, and tissue eosinophilia. Using two distinct mouse models of atopic dermatitis, we show that expression of retinoid-related orphan receptor α (RORα) in skin-resident T regulatory cells (T<sub>regs</sub>) is important for restraining allergic skin inflammation. In both models, targeted deletion ...[more]

PMID: 29500225

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Project description:AimsRetinoic acid receptor-related orphan nuclear receptor ?t (ROR?t) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that ROR?t plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of ROR?t in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated.Methods and resultsMI was generated by ligating coronary artery. The expression of ROR?t and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that ROR?t-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that ROR?t-expressing cells were released from the spleen at day 1 after MI. Though ROR?t-expressing cells in spleen expressed ??TCR or CD4, ??TCR+ cells were major population of ROR?t-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of ROR?t-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at ROR?t locus (ROR?t+/- mice), which physiologically showed reduced expression of ROR?t mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in ROR?t+/- mice than wild-type (WT) mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in ROR?t+/- mice 7 days after MI (Injured area: ROR?t+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: ROR?t+/-; 61.8±4.8%, WT; 49.6±5.1%), accompanied by exacerbation of cardiac function (fractional shortening: ROR?t+/-; 32.9±2.9%, WT; 38.3±3.6%). Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in ROR?t+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of ROR?t, IL-17A, IL-17F and IL-23 receptor (IL-23R) mRNA and protein expression of IL-10 were decreased in ROR?t+/- hearts.ConclusionsHeterozygous deletion of ROR?t gene resulted in aggravated cardiac remodeling, accompanied by reduced capillary density, after MI, suggesting that ROR?t-expressing cells contribute to tissue repair in infarcted myocardium.

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ROR?-expressing T regulatory cells restrain allergic skin inflammation.

Publications

RORα-expressing T regulatory cells restrain allergic skin inflammation.

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