Calcium oxalate (CaOx) stones are the most prevalent urological calculi with high incidence and recurrence. Effective preventive drugs remain lacking because of unclear pathogenesis. Although the imbalance of the dual renin-angiotensin system (RAS) axes is closely linked to oxidative stress and autophagy, its role in CaOx stone formation remains undefined. In vitro, human renal tubular epithelial cells were stimulated with CaOx crystals, with siRNA-mediated AT1R or MasR knockdown or pretreatment with Ang Ⅱ, Ang-(1–7), antioxidant Nacetylcysteine (NAC) or autophagy inhibitor 3-methyladenine (3-MA). RAS components, oxidative stress markers, autophagy-related proteins, stone-related proteins and crystal adhesion were detected. In vivo, a mouse CaOx stone model was induced by intraperitoneal glyoxylic acid injection, with adeno-associated virus-mediated AT1R or MasR knockdown. The above indicators and renal crystal deposition were evaluated. CaOx crystals significantly activated the ACE/Ang Ⅱ/AT1R axis and inhibited the ACE2/Ang-(1–7)/MasR axis in vitro and in vivo, causing intrarenal RAS imbalance. CaOx crystals induced NOX2/4-mediated oxidative stress and AMPK/mTOR-dependent autophagy, which formed a mutually reinforcing loop to upregulate stone-related proteins (OPN, CD44, MCP-1). Activating the ACE/Ang Ⅱ/AT1R axis with Ang Ⅱ exacerbated these pathological changes, while AT1R knockdown alleviated them; conversely, activating the ACE2/Ang-(1–7)/MasR axis with Ang-(1–7) exerted protective effects, whereas MasR knockdown worsened injury. In vivo findings corroborated these results. The ACE/Ang Ⅱ/AT1R axis plays a pathogenic role in CaOx stone formation, whereas the ACE2/Ang-(1–7)/MasR axis exerts a protective effect. Restoring this intrarenal RAS balance represents a promising therapeutic strategy against CaOx stones.
Macrophages represent a heterogeneous cell population in the kidney. However, macrophage subsets and their role in endotoxemia-induced acute kidney injury (AKI) remain elucidated. Single-cell RNA sequencing was performed to identify macrophage subpopulations in mouse kidney following lipopolysaccharide (LPS) challenge. AKI was induced by LPS treatment or renal ischemia reperfusion injury in wild-type or S100a9-/- mice. Silencing or overexpression of S100a9 was carried out to assess its function and contribution to LPS-induced inflammation and AKI. In addition, bone marrow cells from S100a9-/- mice were injected into the recipient mice to determine the effect of S100a9 deletion in macrophage differentiation and renal inflammatory injury. By using single-cell RNA sequencing, we identified a unique S100a8/a9+Ly6chigh proinflammatory macrophage subpopulation in mouse kidney following LPS challenge. LPS administration induced the infiltration of Ly6c+ macrophages into kidney tissues and significantly upregulated the expression of S100a8 and S100a9. S100a9 deletion downregulated S100a8 expression, decreased CD11b+Ly6chigh macrophages, and suppressed proinflammatory cytokine production in the kidney, attenuating LPS or ischemia reperfusion-induced renal inflammation and AKI. Bone marrow transplantation from S100a9-/- mice donors, but not from wild-type mice donors, reduced infiltration of CD11b+Ly6chigh macrophages and renal inflammatory injury. S100a8/a9 overexpression activated the nuclear factor-κB signaling pathway and promoted the production of proinflammatory cytokines in macrophages. S100a8/a9 plays a regulatory role in CD11b+Ly6chigh macrophage population differentiation, contributing to endotoxemia-induced AKI. S100a8/a9 blockade may be a novel therapeutic strategy for the prevention or attenuation of AKI.
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but can cause immune-related adverse events, including potentially severe cardiovascular toxicities. Although rare, immune checkpoint inhibitor-associated myocarditis (ICIM) can present early and may be rapidly fatal, posing a significant challenge at the crossroads of oncology, immunology, and cardiology. This review synthesizes emerging clinical and experimental evidence to refine understanding of risk factors for immune checkpoint inhibitor-associated myocarditis and to outline a practical clinic-to-bench framework linking surveillance and diagnostic decision-making to pathogenic cellular programs. We highlight the cardiac immune microenvironment as a network of multicellular interactions in which cytotoxic T cells and inflammatory myeloid subsets engage with cardiomyocytes, endothelial cells, and fibroblasts through reinforcing feedback loops. Specifically, interferon-γ (IFN-γ)-driven myeloid activation and chemokine programs (CXCR3-CXCL9/10, CXCL16-CXCR6) coordinate immune cell trafficking and promote tissue injury, while stress-related cell death pathways can trigger innate immune sensing via the cGAS-STING axis. Current management remains centered on early recognition and corticosteroid-based immunosuppression, but emerging mechanistic insights reveal opportunities to improve therapy by targeting immune cell trafficking and inflammatory amplification pathways. Together, these advances support a more integrated cardio-oncology approach to ICIM, in which mechanistic insights inform risk stratification, earlier diagnosis, and the development of more precise immunomodulatory therapies.
Intervertebral disc degeneration (IVDD) links cellular stress to persistent sterile inflammation, but the initiating role of misplaced DNA remains uncertain. This review examines mitochondrial DNA (mtDNA) and other self-DNA through a source–compartment–sensor–output framework. Cytosolic DNA can engage cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling, whereas endolysosomal DNA can engage Toll-like receptor 9 (TLR9). Disc-cell experiments and induced animal models support contributions to inflammatory signaling and pyroptotic injury. Genetic findings vary across aging models, limiting universal claims about STING-driven degeneration. We distinguish resident-cell responses from immune-cell recruitment, pathological stress from physiological adaptation, and experimental pathway dependence from disease initiation. We also assess extracellular nucleic-acid capture as preliminary intervention evidence without assuming that native matrix retention or endogenous nuclease failure has been established. The framework identifies where direct disc evidence supports a mechanism and where trafficking, causality or clearance remains unresolved. Priorities include source-selective perturbation, temporal and compartment-resolved measurements, and independent structural and pain-related outcomes. Clinical translation requires validation beyond preclinical structural improvement.
Chronic inflammation exerts paradoxical effects in breast cancer, inducing growth arrest while sustaining tumor progression. However, how autocrine and paracrine inflammatory cytokine induced senescence integrates with tumor-promoting behaviour remains unclear. Here, we identify a reciprocal IL-1β/IL-6 circuit that links inflammatory cues, epigenetic remodeling and cytokine induced senescence in luminal breast cancer cells. Following treatment with IL-1β and IL-6, MCF-7 cells were examined using cell-cycle, apoptosis, reactive oxygen species flow cytometry assays, and senescence assays; RNA sequencing; global DNA methylation quantification; methylation-specific PCR; ChIP-qPCR for histone marks; cytokine ELISA; and western blotting for DNMTs and STAT3/AKT/NF-κB signaling proteins. The kinetics of IL-1β and IL-6 signaling were examined using receptor antagonism and pharmacological inhibition. IL-1β induced senescence characterized by G0/G1 arrest, elevated SA-β-gal activity, ROS accumulation and absence of apoptosis. Transcriptomic profiling revealed cell-cycle regulator repression, enrichment of senescence-associated signatures and a pro-inflammatory secretory phenotype. Mechanistically, IL-1β induced increased DNMT1 and DNMT3A expression, elevated global DNA methylation, induced promoter-specific DNA methylation (IL-15, HMGB2) and histone mark remodeling (IL-6, IL1RN, BCL2,BAX) at inflammatory, senescence, and apoptotic loci. IL-1 receptor antagonism attenuated these effects. IL-6 induced downstream of IL-1β, in turn activated STAT3, increased DNMT1 and DNMT3B expression, amplified IL-1β expression and tumor-promoting phenotypes, while sustaining the IL-1β induced senescence state. IL-6R blockade disrupted this axis and reduced tumor-promoting effects. An IL-1β/IL-6 inflammatory loop drives epigenetic remodeling associated with cytokine induced senescence while promoting tumor-supportive signaling. IL-1β initiates the senescence program, whereas IL-6 reinforces and sustains this state through STAT3/DNMT signaling, highlighting inflammatory cytokine signaling pathways as potential therapeutic targets for breast cancer therapy.
