Background: Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype and function of so-called tissue Tregs in the heart remain unclear. Methods: In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury (I/R injury) or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA-sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or I/R injury. Photoconversion, parabiosis, single-cell TCR sequencing and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin (IL)-33/ST2 axis and secreted acidic cysteine rich glycoprotein (Sparc), a molecule upregulated in heart Tregs, was further evaluated in functional assays. Results: We showed that Tregs were highly enriched in the myocardium of MI, I/R injury and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts compared to their lymphoid counterparts including heart draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly due to recruitment from circulating Treg pool, while local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected TCR of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, Helios high Nrp-1 high phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4 + T cells (Tconvs), proved by the analysis of TCR repertoires and Tconvs adoptive transfer experiments. Notably, the IL-33/ST2 axis was essential for sustaining heart Treg populations. Finally, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone. Conclusions: We identified and characterized a phenotypically and functionally unique population of heart Tregs, which may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.
The activation of mitochondrial H(2)O(2)-sensitized CaSR by extracellular Ca(2+) mediates HICI in PASMCs and, thus, initiates HPV.
BackgroundMonocrotaline has been widely used to establish an animal model of pulmonary hypertension. The molecular target underlying monocrotaline‐induced pulmonary artery endothelial injury and pulmonary hypertension remains unknown. The extracellular calcium–sensing receptor (CaSR) and particularly its extracellular domain hold the potential structural basis for monocrotaline to bind. This study aimed to reveal whether monocrotaline induces pulmonary hypertension by targeting the CaSR.Methods and ResultsNuclear magnetic resonance screening through WaterLOGSY (water ligand‐observed gradient spectroscopy) and saturation transfer difference on protein preparation demonstrated the binding of monocrotaline to the CaSR. Immunocytochemical staining showed colocalization of monocrotaline with the CaSR in cultured pulmonary artery endothelial cells. Cellular thermal shift assay further verified the binding of monocrotaline to the CaSR in pulmonary arteries from monocrotaline‐injected rats. Monocrotaline enhanced the assembly of CaSR, triggered the mobilization of calcium signaling, and damaged pulmonary artery endothelial cells in a CaSR‐dependent manner. Finally, monocrotaline‐induced pulmonary hypertension in rats was significantly attenuated or abolished by the inhibitor, the general or lung knockdown or knockout of CaSR.ConclusionsMonocrotaline aggregates on and activates the CaSR of pulmonary artery endothelial cells to trigger endothelial damage and, ultimately, induces pulmonary hypertension.
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