Sen Chen,Hui Lin,Haodi Gu,Xinrou Yu,Junjie Xiang,Lili Xu,Gang Ye,Yue Shan,Yun Wang
Introduction Sepsis-induced cardiomyopathy (SIC) is a rapidly advancing condition associated with a poor prognosis due to the lack of effective treatments. Neutrophil extracellular traps (NETs), however, act as a double-edged sword in the innate immune response during sepsis. N-formyl methionine (fMet) has been documented to induce NETs in inflammatory conditions, yet its clinical significance and biological function in SIC remain unclear. In this study, we investigated whether fMet induces excessive NETs, thereby promoting SIC. Methods and results Clinically, serum fMet levels were quantified using ELISA, revealing a significant elevation in patients with SIC compared to non-sepsis patients and healthy controls. The fMet levels were positively correlated with the NETs-related markers myeloperoxidase (MPO) and double-stranded DNA (dsDNA) in patients with SIC. Treatment with lipopolysaccharide and fMet increased NET formation in human neutrophils and upregulated the expression of formyl peptide receptor 1 (FPR1) and hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, bone marrow-derived neutrophils (BMDNs) were isolated from global FPR1 knockout mice, and FPR1 deficiency in BMDNs was found to suppress NETosis. The cecal ligation and puncture (CLP) model was employed to induce SIC in mice and we found knockout of FPR1 improved outcomes in CLP mice, as evidenced by survival benefit, increased cardiac function, attenuated cytokine storm, reduced neutrophil infiltration, improved mitochondrial function and suppressed NETosis, compared with those of wild-type (WT) mice. In addition, treatment with FPR1 inhibitor HCH6–1 improved cardiac outcome and inhibits NETosis in CLP mice. Conclusion These data reveal the role of fMet-mediated FPR1/HIF-1α activation in promoting SIC through the NETosis, indicating novel therapeutic strategy for SIC.
Oxidative stress-induced endoplasmic reticulum stress (ERS) plays a pivotal role in the senescence and degeneration of nucleus pulposus cells, and currently, no effective therapeutic options exist for intervertebral disc degeneration. The limited self-repair capacity of nucleus pulposus cells hampers their ability to recover, even after the removal of oxidative stressors. Consequently, the identification of cytokines capable of effectively mitigating ERS induced by cellular oxidative stress is of paramount importance for the repair of intervertebral discs. Calreticulin (CRT), an endoplasmic reticulum-resident protein, has been shown in recent studies to promote cell proliferation and collagen secretion; however, its role in intervertebral disc repair remains underexplored. This study demonstrated that CRT can repair damaged nucleus pulposus cells through two independent pathways: 1. Reducing the cell ERS condition to alleviate the rate of cell senescence; 2. Activating the FPR1/PI3K/AKT pathway to promote cell proliferation. Furthermore, a targeted endoplasmic reticulum lipid nanoparticle encapsulating CRT was successfully developed for material-based repair of damaged intervertebral discs. This novel approach provides a promising strategy for the repair of intervertebral disc degeneration.
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