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Caspase-1 inhibition ameliorates murine acute graft versus host disease by modulating the Th1/Th17/Treg balance.
- Source :
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International Immunopharmacology . May2021, Vol. 94, pN.PAG-N.PAG. 1p. - Publication Year :
- 2021
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Abstract
- • Ac-YVAD-CMK reduces the pathological damage of recipient tissues. • Ac-YVAD-CMK improves the GVHD in a murine model of aGVHD. • Ac-YVAD-CMK reduces the expression of IL-1β, IL-18, and HMGB1 in recipients. • Ac-YVAD-CMK modulates the balance of Th1/Th17/Treg subsets in recipients. Our previous studies have implicated Caspase-1 signaling in driving the proinflammatory state of acute graft versus host disease (aGVHD). Therefore, we aimed to elucidate the mechanism of Caspase-1 in in murine models of aGVHD through specific inhibition of its activity with the decoy peptide Ac-YVAD-CMK. We transplanted bone marrow from donor C57BL/6 (H-2b) mice into recipient BALB/c (H-2Kd) mice and randomized the recipients into the following treatment cohorts: (1) allogeneic hematopoietic stem cell transplantation and splenic cell infusion control (PBS group); (2) low dose Ac-YVAD-CMK (AC low group); (3) and high dose Ac-YVAD-CMK (AC high group). Indeed, we observed that Caspase-1 inhibition by Ac-YVAD-CMK ameliorated pathological damage and inflammation in the liver, lungs, and colon elicited by aGVHD. This was associated with reduced mortality secondary to aGVHD. Mechanistically, we found that Caspase-1 inhibition modulated donor T cell expansion, restored the balance of Th1/Th17/Treg subsets, and markedly decreased serum levels and aGVHD target organ mRNA expression of IL-1β, IL-18, and HMGB1. Thus, we demonstrate that inhibition of Caspase-1 by Ac-YVAD-CMK mitigates murine aGVHD by regulating Th1/Th17/Treg balance and attenuating its characteristic proinflammatory state. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15675769
- Volume :
- 94
- Database :
- Academic Search Index
- Journal :
- International Immunopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 149968923
- Full Text :
- https://doi.org/10.1016/j.intimp.2021.107503