Treg expansion with trichostatin A ameliorates kidney ischemia/reperfusion injury in mice by suppressing the expression of costimulatory molecules.

Ryohei Yamamoto, Mitsuru Saito, Takuro Saito, Ryuichiro Sagehashi, Atsushi Koizumi, Taketoshi Nara, Sohei Kanda, Kazuyuki Numakura, Shintaro Narita, Takamitsu Inoue, Shigeru Satoh, Tomonori Habuchi

Transplant immunology 2020 Dec

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Innate immune reactions are believed to be associated with ischemia/reperfusion injury (IRI), and IRI might be treatable by expanding regulatory T cells (Tregs), which can suppress the excessive responses of the immune system. Organ IRI is known to be closely involved in the expression of costimulatory molecules. The present study aimed to assess whether Tregs endogenously expanded by the administration of trichostatin A (TsA), a histone deacetylase inhibitor, could reduce renal IRI and to clarify their association with the expression of costimulatory molecules in a murine model. In this study, the wild-type mice used for an IRI model were randomly divided into the following four treatment groups: TsA group, DMSO group (control), DMSO+PC61 group, and TsA + PC61 group. Renal injury in the early phase after IRI was ameliorated in the TsA group (increased Tregs) when compared with the other groups. After renal IRI, both the mRNA and the protein levels of anti-inflammatory cytokines, IL-10 and TGF-β in the kidney and spleen were significantly higher in the TsA group than in the other groups, whereas the IL-6 levels were significantly lower in the TsA group than in the other groups. These results were offset by the administration of PC61, supporting that the renoprotective effect of TsA in this study is Treg dependent. mRNA expression levels of CD80, CD86, and ICAM-1 were lower in the TsA group, consistent with Treg control of injury through costimulatory molecules. Our findings suggest that endogenously expanded Tregs coordinate postischemic immune responses and decrease the expression of costimulatory molecules after renal IRI, and thus, they might ameliorate renal IRI. TsA administration for expanding Tregs is a promising therapeutic strategy for renal IRI. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Ryohei Yamamoto, Mitsuru Saito, Takuro Saito, Ryuichiro Sagehashi, Atsushi Koizumi, Taketoshi Nara, Sohei Kanda, Kazuyuki Numakura, Shintaro Narita, Takamitsu Inoue, Shigeru Satoh, Tomonori Habuchi. Treg expansion with trichostatin A ameliorates kidney ischemia/reperfusion injury in mice by suppressing the expression of costimulatory molecules. Transplant immunology. 2020 Dec;63:101330