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Low-level tragus stimulation alleviates sepsis-associated acute kidney injury by promoting renal M2 macrophage polarization.

ABSTRACT: Background: Low-level tragus stimulation (LL-TS) can reduce acute renal injury in sepsis and improve survival rates. However, the underlying molecular mechanisms remains unknown. Renal macrophages that contributed to AKI in sepsis under low-level tragus stimulation were characterized. Methods: Mice were randomly assigned to five groups following diverse treatments: Control, Sham, Sepsis, LL-TS + sepsis, and LL-TS + sepsis + Methyllycaconitine citrate (MLA). Blood creatinine testing and hematoxylin and eosin (HE) staining were used to assess kidney injury. Single-cell RNA sequencing were used to profile renal macrophages from CD45+ cells in mouse kidney. Western blot, immunofluorescence and HE staining were performed to verify the level of the alpha7 nicotinic acetylcholine receptor (α7nAChR) or interleukin-1β expression in kidney. Results: HE staining and blood creatinine testing of renal tissue indicated that LL-TS alleviated renal injury in mice with sepsis-associated acute kidney injury (AKI). A map of the renal cellular landscape was generated to identify macrophages that contributed to AKI in sepsis under LL-TS. Pseudo-timing analysis showed that LL-TS played an anti-inflammatory role by promoting renal monocyte conversion into M2 macrophages. Moreover, LL-TS significantly increased α7nAChR expression and decreased interleukin-1β expression in renal tissues. Conclusions: LL-TS alleviated sepsis-associated AKI by increasing α7nAChR expression and M2 macrophage polarization which promotes the anti-inflammatory process in sepsis. The results suggests that LL-TS may serve as a potential therapeutic strategy for sepsis-induced kidney dysfunction, ultimately improving patient outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE300487 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Background: Sepsis can lead to multiple organ damage, and the heart is one of the most vulnerable organs. Vagal nerve stimulation can reduce myocardial injury in sepsis and improve survival rate. However, the relative effect of disparate cell populations on sepsis induced myocardial dysfunction and the low-level tragus stimulation on it, remain unclear. Methods: We used the cardiac single-cell transcriptomic strategy to characterize the cardiac cell population and the network of cells that forms the heart. And we selected all cardiac macrophage from CD45+ cells using single-cell mRNA sequencing data. Then we used echocardiography performing, western blot and immunofluorescence and immunohistochemical technology to verify the data of the single-cell mRNA sequencing results. Results: In single-cell mRNA sequencing data, our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to sepsis induced myocardial dysfunction under low-level tragus stimulation. Pseudo timing analysis in single-cell sequencing showed that low level vagal nerve stimulation could induce the transformation of cardiac monocytes into M2 macrophages and play an anti-inflammatory role. After low-level tragus stimulation, the expression of α7nAChR in the heart tissue increased significantly. Echocardiography showed that low-level tragus stimulation could improve the cardiac function of septic myocardial injury of the mice. Comparing with the sepsis group, the expression of interleukin-1β in heart tissue of the mice in sepsis with low-level tragus stimulation group is significantly lower. Conclusion: Low-level tragus stimulation can improve sepsis-induced myocardial dysfunction by promoting cardiac monocytes to M2 macrophages. Goal of the study: In the present study, we aimed to screen macrophages, their crosstalk with other cells, and macrophages associated with cardiac injury and further verify their origins and roles in the septic myocardial injury process and low-level tragus stimulation (LL-TS) to treat septic myocardial dysfunction.

Project description:Sepsis is a severe and dysregulated inflammatory disease that often precedes the development of acute kidney injury (AKI) with consequent worsening outcome. The main characteristics of sepsis-induced AKI include endothelial cell (EC) dysfunction, infiltration of inflammatory cells, glomerular thrombosis, and renal tubular epithelial cells (RTEC) injury. Numerous studies have demonstrated that mammalian target of rapamycin (mTOR) activation has been implicated in the initiation and progression of renal injury in course of sepsis. However, little is known, about the molecular basis of mTOR role in EC and RTEC dysfunction. Here, we evaluate whether mTOR inhibition by Rapamycin (Rp) as potential strategy to ameliorate renal function and dissected the molecular mechanisms involved. In a mouse model of lipopolysaccharide (LPS)-induced AKI , LPS injection led to a time-dependent increase of serum creatinine and significant morphological changes in renal parenchyma associated with increased collagen deposits and endothelial dysfunction. Interestingly, Rp treatment significantly decreased creatine levels and preserved renal parenchyma, counteracting Endothelial-to mesenchymal transition (EndMT) process and early fibrosis through the inhibition of ERK pathway. Next, we examined the effects of LPS-TLR4 interaction in RTECs. Through a whole-genome DNA methylation analysis in cultured RTEC, we found that LPS induced aberrant methylation, particularly in regions involved in premature aging. The most represented genes were CD39 and WFS1. LPS stimulation of RTEC led to up-regulation of SA-β Gal and cell cycle arrest markers such as p21. In accordance, in endotoxemic mice, we found a decreased expression of CD39 concurrent with Klotho down-regulation. Administration of Rp exerted anti-aging effects in endotoxemic mice, preserving CD39 and Klotho expression. In conclusion, we demonstrated that mTOR inhibition could offer novel strategies to protect endothelial and tubular compartment from accelerated aging and fibrosis thus counteracting the progression to chronic kidney disease.

Project description:Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life threatening sequalae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprised of ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtLLysM-/-) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, while sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evident by a rise in serum creatinine and cystatin C, and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy post-sepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NFkB or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, loss of FtL did not influence sepsis pathogenesis.

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Low-level tragus stimulation alleviates sepsis-associated acute kidney injury by promoting renal M2 macrophage polarization.

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