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.
BackgroundLodging in rice production often limits grain yield and quality by breaking or bending stems. Excessive nitrogen (N) fertilizer rates are the cause of poor lodging resistance in rice, but little is known about the effect of top-dressing N application rates on the mechanical strength of japonica rice plants, especially how the anatomical structure in culms is affected by N. In this study, field experiments on two japonica rice varieties with three top-dressing N application rates, 0 kg N ha−1 (LN), 135 kg N ha−1 (MN), and 270 kg N ha−1 (HN) as urea, were conducted. Wuyunjing23, a lodging-resistant japonica rice cultivar and W3668, a lodging-susceptible japonica rice cultivar were used. The lodging index, breaking strength, morphological and anatomical traits in culms were measured in this study.ResultsThe visual lodging rate in japonica rice differed remarkably between genotypes and top-dressing N treatments. The higher lodging index of rice plants was primarily attributed to the weak breaking strength of the lower internodes. The longer elongated basal internodes were responsible for higher plant height and a higher lodging index. Correlation analysis showed that breaking strength was significantly and positively correlated with the thickness of the mechanical tissue but was significantly and negatively correlated with the inner diameter of the major axis (b2). With increasing top-dressing N rates, the sclerenchyma cells of the mechanical tissues and the vascular bundles of the Wuyunjing23 cultivar varied little. The plant height, inner diameter of the minor axis (a2) and b2 increased significantly, but the area of the large vascular bundle (ALVB) and the area of the small vascular bundle (ASVB) decreased significantly and resulted in lower stem strength and a higher lodging index under higher top-dressing N conditions. The culm diameter of the W3668 cultivar increased slightly with no significant difference, and the sclerenchyma cells in the mechanical tissues and vascular bundles showed deficient lignifications under high top-dressing N conditions. Moreover, the ALVB and the ASVB decreased significantly, while the area of air chambers (AAC) increased rapidly.ConclusionsAn improvement in the lodging resistance of japonica rice plants could be achieved by reducing the length of the lower internodes, decreasing the inner culm diameter and developing a thicker mechanical tissue. Top-dressing N application increased the plant height and inner culm diameter and decreased the ALVB and the ASVB of the Wuyunjing23 cultivar and caused deficient lignified sclerenchyma cells, lowered the ALVB and the ASVB, and increased the AAC of the W3668 cultivar resulting in weaker stem strength and a higher lodging index.
Objective— Inflammation occurs during the progression of abdominal aortic aneurysm (AAA). IL (interleukin)-33 is a pleiotropic cytokine with multiple immunomodulatory effects, yet its role in AAA remains unknown. Approach and Results— Immunoblot, immunohistochemistry, and immunofluorescent staining revealed increased IL-33 expression in adventitia fibroblasts from mouse AAA lesions. Daily intraperitoneal administration of recombinant IL-33 or transgenic IL-33 expression ameliorated periaorta CaPO 4 injury- and aortic elastase exposure–induced AAA in mice, as demonstrated by blunted aortic expansion, reduced aortic wall elastica fragmentation, enhanced AAA lesion collagen deposition, attenuated T-cell and macrophage infiltration, reduced inflammatory cytokine production, skewed M2 macrophage polarization, and reduced lesion MMP (matrix metalloproteinase) expression and cell apoptosis. Flow cytometry analysis, immunostaining, and immunoblot analysis showed that exogenous IL-33 increased CD4 + Foxp3 + regulatory T cells in spleens, blood, and aortas in periaorta CaPO 4 -treated mice. Yet, ST2 deficiency muted these IL-33 activities. Regulatory T cells from IL-33–treated mice also showed significantly stronger activities in suppressing smooth muscle cell inflammatory cytokine and chemokine expression, macrophage MMP expression, and in increasing M2 macrophage polarization than those from vehicle-treated mice. In contrast, IL-33 failed to prevent AAA and lost its beneficial activities in CaPO 4 -treated mice after selective depletion of regulatory T cells. Conclusions— Together, this study established a role of IL-33 in protecting mice from AAA formation by enhancing ST2-dependent aortic and systemic regulatory T-cell expansion and their immunosuppressive activities.
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