Acute respiratory distress syndrome (ARDS) remains difficult to treat due to its heterogeneous etiology. In this study, a mouse model of intratracheal lipopolysaccharide (LPS) instillation was used to investigate age- and sex-dependent immune responses. After six hours of LPS exposure and one hour of mechanical ventilation, immune cell subtypes as well as mRNA and protein expression were analyzed. Aged mice exhibited a basal pro-inflammatory immune signature already under sham conditions, whereas young mice displayed a more balanced response with parallel pro- and anti-inflammatory mechanisms. Notably, aged female LPS treated mice exhibited an exclusively pro-inflammatory response. UMAP analysis revealed distinct clustering according to age, sex, and treatment, while aged male mice formed isolated clusters. These findings highlight the importance of considering age- and sex-specific therapeutic strategies for ARDS treatment.
Interleukin-35 (IL-35) exerts immunosuppressive effects in rheumatoid arthritis (RA), but its direct impact on synovial fibroblasts (SFs) remains unclear. This study aimed to redefine the role of IL-35 in RA by uncovering its therapeutic mechanism through the induction of STING-dependent synovial fibroblast senescence. We first observed dysregulated IL-35 signaling in RA patients. In a collagen-induced arthritis (CIA) mouse model, recombinant IL-35 treatment effectively alleviated disease severity, reducing clinical scores, joint swelling, and pro-inflammatory cytokines. The pivotal discovery emerged from in vitro experiments: IL-35, but not TNF-α, directly promoted cellular senescence in RA synovial fibroblasts (RASFs). Mechanistically, IL-35 signaled through the glycoprotein 130 (GP130) receptor to activate the cGAS-STING-TBK1-IRF3 pathway, leading to upregulated senescence markers (p16, p21, p53). This STING activation was essential, as its inhibition abolished the pro-senescent effect. Crucially, in vivo knockdown of endogenous IL-35 exacerbated arthritis, and this aggravation was rescued by co-treatment with an IRF3 agonist. Our findings establish a novel protective axis in which IL-35 activates the STING pathway to drive RASFs into a senescent state, thereby inhibiting their pathogenic activity and ameliorating RA progression. Our work identifies IL-35 as a unique cytokine that confers protection by driving STING-dependent senescence in RASFs, highlighting this axis as a novel therapeutic target for RA.
Chronic inflammatory skin disorders are characterized by persistent skin inflammation, impaired barrier function, and frequent recurrence, all of which substantially reduce patients’ quality of life. Traditional studies attribute the pathogenesis of these diseases to immune dysregulation, whereas new evidence indicates that cellular senescence is a key risk factor and a mechanism underlying disease progression. Cellular senescence, defined by irreversible cell cycle arrest, is accompanied by a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and DNA damage. This review systematically outlines the hallmarks, regulatory mechanisms, and inducers of cellular senescence, elucidates its pathological role in representative inflammatory skin disorders, and evaluates emerging therapeutic strategies that target senescent cells. By elucidating the dynamic crosstalk between cellular senescence and inflammatory skin diseases, this review aims to identify novel therapeutic targets and provide new insights into their diagnosis, treatment, and prevention.
Long-term care facility (LTCF) residents represent one of the populations most vulnerable to SARS-CoV-2 infection and have experienced repeated vaccination and natural viral exposure since the beginning of the COVID-19 pandemic. The long-term dynamics of humoral and cellular immunity in this population remain incompletely characterized. In this multicenter longitudinal study, SARS-CoV-2-specific antibody responses were monitored in LTCF residents over 12 months. A total of 388 residents from LTCF across five Italian regions were enrolled and stratified according to receipt of the SARS-CoV-2 XBB.1.5 mRNA booster during the 2023–2024 vaccination campaign. In a subgroup of residents, peripheral B-cell phenotypes and Spike-specific memory B cells were characterized by flow cytometry and compared with those of younger healthcare workers vaccinated with the same formulation. Anti-Spike IgG titers peaked in residents who received the XBB.1.5 booster and subsequently declined over time, consistent with contraction of vaccine-induced humoral responses. In contrast, individuals who did not receive the booster maintained lower but stable antibody levels. Anti-nucleocapsid seroconversion and clinically diagnosed intercurrent infections occurred at broadly comparable observed rates in boosted and non-boosted residents, suggesting a comparable incidence of SARS-CoV-2 infection during follow-up. Regarding B-cell-mediated immunity, LTCF residents exhibited age-associated remodeling of the B-cell compartment, with reduced total B-cell frequencies but preserved antigen-experienced memory populations. Despite declining circulating antibodies, Spike-specific memory B-cell frequencies remained stable. A late increase in anti-Spike titers coincided with rising anti-nucleocapsid seropositivity, suggesting reactivation of immune memory following natural viral exposure. These findings indicate that repeated vaccination and natural exposure generate durable immunological memory in LTCF residents. In highly exposed populations, immune maintenance may increasingly rely on reactivation of memory responses rather than persistently high antibody titers.
As the largest and most externally exposed organ, the skin is particularly vulnerable to aging, rendering skin aging a widespread clinical and aesthetic concern. Driven by both intrinsic and extrinsic factors, skin aging is characterized by progressive functional decline and structural remodeling that compromise barrier integrity, disrupt dermal homeostasis, and ultimately diminish quality of life. At the upstream regulatory level, skin aging-associated epigenetic modifications drive epigenetic drift that compromises transcriptional fidelity and primes cells toward senescence. At the cellular level, regulatory mechanisms converge on cellular senescence and profound mitochondrial remodeling. At the microenvironmental level, the failure of senescent cell clearance (immunosenescence) and the emergence of a chronic pro-inflammatory milieu (inflammaging) create a self-reinforcing immune–inflammatory axis. This axis exacerbates cytokine production, extracellular matrix remodeling, and progressive tissue degeneration. We further highlight emerging mechanism-targeted interventions, including epigenetic and mitochondrial modulators, senotherapeutics, biologics, immunotherapies, regenerative and device-based therapies. A deeper understanding of these interconnected molecular mechanisms and targeted therapies may offer a roadmap for future therapeutic innovation and translational research in skin aging.
