One of the hallmarks of aging is chronic inflammation or “inflammaging”, characterized by an increase in pro-inflammatory biomarkers observed during aging. Furthermore, immune responsiveness to stimulation is often defective. Neutrophils are the most abundant immune cell type in the circulation, acting as an early responder to infections. We performed an exploratory study to determine the effect of aging on neutrophil function. Participants in this study belonged to three age groups: young adults (20–30 y.o.), older adults (55–65 y.o.), and octo/nonagenarians (> 85 y.o.). Flow cytometry was performed to determine neutrophil subsets and baseline activation in the circulation. Neutrophils of older adults and octo/nonagenarians had an increased expression of CD66b compared to young adults. Neutrophil functions such as phagocytosis and NETosis were not affected by aging. Interestingly, ROS production at baseline was increased in older adults compared to young adults and octo/nonagenarians. Furthermore, PMA stimulation assays showed an increased IL-8 expression in older adults and octo/nonagenarians. Using RNA-sequencing, we report an increased expression of LTRs and LINE retrotransposons in neutrophils of old individuals. This was accompanied by an increased expression of interferon response genes: OAS2, IFIT1, and MX1, in older adults and octo/nonagenarians. In conclusion, we observed a more inflammatory profile of neutrophils in the elderly that is associated with interferon pathway activation and chemokine release, potentially induced by reactivation of transposable DNA elements.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by intestinal barrier dysfunction, excessive immune activation, and impaired epithelial homeostasis. Emerging evidence suggests that metabolic dysregulation contributes to disease progression. This study investigated whether human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEVs) alleviate IBD by regulating creatine metabolism through creatine kinase B (CKB)-mediated creatine/phosphocreatine (Cr/PCr) conversion. A dextran sulfate sodium (DSS)-induced murine colitis model and lipopolysaccharide (LPS)-stimulated IEC-6 intestinal epithelial cells were used to evaluate the effects of hucMSC-sEVs on inflammation, apoptosis, barrier integrity, and creatine metabolism. hucMSC-sEVs treatment markedly alleviated colitis and restored intestinal epithelial homeostasis in both in vivo and in vitro settings. Mechanistically, hucMSC-sEVs significantly increased the expression of the creatine metabolism-related molecules SLC6A8 and GATM, while normalizing the inflammation-induced elevation of the Cr/PCr ratio by recovering CKB function. Furthermore, pharmacological inhibition or knockdown of CKB aggravated inflammation, apoptosis, and barrier dysfunction and substantially diminished the protective effects of hucMSC-sEVs. These findings demonstrate that CKB-mediated creatine metabolism is a critical regulator of intestinal epithelial homeostasis during inflammatory injury. hucMSC-sEVs exerts its protective effects, at least in part, by restoring creatine metabolic balance through CKB, highlighting a previously unrecognized metabolic mechanism and a potential therapeutic target for IBD.
Malaria remains a significant global health challenge, particularly in tropical regions, where high morbidity and mortality persist. The need for new therapeutic strategies remains urgent as increasing antimalarial drug resistance threatens treatment efficacy and highlights the need for innovative approaches that target not only the parasite but also host–pathogen interactions. While malaria immunology has traditionally focused on adaptive responses, including T-cell dysfunction, the role of innate immune checkpoints remains underexplored. Among these, CD47- a transmembrane protein best known for delivering a “don't-eat-me” signal to phagocytes has emerged as a potential therapeutic target. This concept is particularly relevant to malaria because Plasmodium infects red blood cells, whose survival and clearance are tightly regulated by CD47–SIRPα signalling.Emerging evidence suggests that CD47 contributes to the regulation of phagocytic clearance of infected red blood cells and may influence inflammatory responses associated with disease severity. Disruption of CD47–SIRPα signalling may enhance host phagocytic responses, promoting clearance of parasitized erythrocytes and potentially improving disease control. This review examines the immunopathological role of CD47 in malaria, evaluates its potential as a host-directed therapeutic target, and discusses the challenges and future directions for translating CD47-targeted strategies into clinical practice. CD47, therefore represents a promising but incompletely validated host-directed therapeutic target, with important translational gaps that must be addressed before clinical application.
Background: Diabetic foot ulcer (DFU) is a serious complication of diabetes, characterized by persistent inflammation and impaired wound healing. Sprouty2 (SPRY2) is a negative regulatory factor of the receptor tyrosine kinase signaling pathway and plays an important role in cell proliferation, migration and differentiation. However, the function of SPRY2 in diabetic wound healing remains unclear. This study aims to explore the regulatory role and mechanism of SPRY2 in diabetic wound healing. Method: This study collected skin tissues from patients with DFU to assess the expression of SPRY2. In SpragueDawley rats, the DFU model was established using streptozotocin, and the sh-SPRY2 lentivirus was injected into the wound site. In vitro, the fibroblasts were treated with 25 mM high glucose. Histology, immunofluorescence, Real-time fluorescence quantitative PCR detection, Western blot, EDU, Wound healing and Transwell assay were employed. Result: The results showed that the expression of SPRY2 was significantly upregulated in the wound tissues of DFU patients. The study found that SPRY2 could inhibit the proliferation and migration of fibroblasts and hinder the wound healing of DFU rats. Furthermore, after knocking down the expression of SPRY2, the proliferation and migration abilities of fibroblasts significantly increased, thereby promoting wound healing in DFU rats. Further studies on its potential mechanism indicated that SPRY2 inhibited the Ras/MAPK pathway, leading to dysfunction of DFU fibroblasts and difficulty in wound healing. Conclusion: In DFU, SPRY2 inhibits the Ras/MAPK pathway to prevent wound healing. This mechanism provides a theoretical basis for targeting SPRY2 to treat wound healing disorders.
