Obesity is a chronic immunometabolic disorder associated with alterations in biological aging pathways and increased risks of type 2 diabetes mellitus, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, neurodegeneration, and cancer. Obesity and chronological aging share several characteristics, including low-grade inflammation, cellular senescence, mitochondrial dysfunction, oxidative stress, epigenetic alterations, and immune remodeling. However, these similarities do not necessarily establish accelerated biological immune aging. This review critically evaluates obesity-associated immunosenescence, metaflammation, and multiorgan dysfunction by examining supporting and conflicting findings, alternative explanations, methodological limitations, and therapeutic evidence. Although experimental and observational studies report alterations in lymphocyte differentiation, innate immune function, inflammatory signaling, and selected biological-age markers, these findings are not uniformly observed across immune-cell populations, tissues, or metabolic phenotypes. Metabolically healthy obesity, tissue-dependent epigenetic aging, and differences between human and animal findings challenge the interpretation of obesity as a universal accelerator of immunosenescence. Furthermore, chronological age, cytomegalovirus infection, sex-related differences, adiposity distribution, and metabolic comorbidities complicate attributing immune alterations specifically to obesity. The proposed immunosenescence–metaflammation–multiorgan dysfunction framework therefore remains a testable mechanistic hypothesis rather than an established causal pathway. Although immune-cell phenotypes, epigenetic clocks, inflammatory mediators, and multi-omics signatures may help characterize obesity-associated immune dysfunction, their specificity, longitudinal validity, and clinical utility remain insufficiently established. Nutritional interventions, exercise, bariatric surgery, and pharmacological treatments can improve selected metabolic and inflammatory outcomes, but these improvements do not necessarily demonstrate sustained reversal of biological immune aging. By critically comparing supportive evidence with contradictory observations and unresolved causal relationships, this review identifies the principal limitations of current mechanistic, biomarker, and therapeutic research. Future studies should prioritize longitudinal immune profiling, direct functional assessment, tissue- and sex-specific analyses, causal validation, and controlled interventions incorporating validated immune-aging endpoints to determine whether premature immune aging is a measurable and therapeutically modifiable consequence of obesity.
Biologic therapy has transformed psoriasis into a clinically controllable disease, yet skin clearance does not guarantee resolution of the systemic inflammation and vascular dysfunction that drive cardiovascular risk in this population. We hypothesize that interleukin (IL)-23-axis-proximal cytokines and C-reactive protein (CRP) mark two distinct, dissociable inflammatory compartments in psoriasis: IL23-axis-proximal signaling predominantly governs cutaneous disease activity and microvascular endothelial function, whereas CRP integrates a broader cardiometabolic burden and tracks macrovascular recovery. We distinguish IL23-axis-proximal cytokines (IL23, IL17a, IL22), whose production is largely confined to lesional skin, from shared effector cytokines (TNF-α, IFN-γ, IL1, and IL6), which also arise from adipose tissue and other systemic sources. This model generates two falsifiable predictions: (1) IL23 blockade will improve cutaneous microvascular endothelial function in proportion to suppression of IL23-axis-proximal signaling and out of proportion to any change in CRP, and (2) persistent CRP elevation despite adequate skin clearance will identify patients with blunted macrovascular recovery even when IL23-axis-proximal signaling is suppressed. Because IL6 is a node shared by cutaneous and adipose inflammation, the two compartments are coupled, and we therefore state the model in relative rather than absolute terms: quantitative dissociation, not statistical independence. If confirmed, this compartmentalized model would explain why near-complete skin clearance under biologic therapy, including IL23 blockade, does not uniformly normalize cardiovascular risk, and would offer two complementary, mechanism-specific biomarkers, rather than skin clearance alone, for monitoring vascular recovery after psoriasis treatment. We outline the rationale for this hypothesis and a longitudinal biomarker-imaging design capable of refuting it.
Alzheimer’s disease (AD) is increasingly recognized as a multicellular neuroimmune disorder in which proteostatic failure, metabolic dysfunction, and sustained glial activation interact to accelerate synaptic loss. This narrative review examines endoplasmic reticulum (ER) stress in astrocytes as a mechanistic link among the unfolded protein response (UPR), neuroinflammation, mitochondrial dysfunction, and neurodegeneration. The three canonical UPR branches, mediated by protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), initially reduce protein-folding burden and reinforce ER quality control. When stress persists and adaptive capacity becomes insufficient, sustained PERK and IRE1 signaling may favor apoptosis, inflammatory transcriptional programs, cytokine production, calcium dyshomeostasis, and oxidative injury, whereas ATF6 remains predominantly associated with proteostatic reinforcement in a context-dependent manner. In astrocytes, persistent UPR activation may impair neuronal metabolic support, synaptogenic signaling, and astrocytic contributions to neurovascular homeostasis while promoting complement component 3 (C3) expression and bidirectional inflammatory crosstalk with microglia. ER-mitochondria contact sites further integrate calcium transfer, reactive oxygen species generation, bioenergetic failure, and intrinsic apoptotic signaling. Experimental evidence therefore supports a self-reinforcing neuroglial circuit in which astrocytic ER stress is proposed to function as an amplifier rather than merely a consequence of AD pathology. Therapeutic strategies targeting UPR signaling, chemical chaperones, extracellular vesicles, gene modulation, and cell-selective delivery systems remain under investigation, and their translation will require temporally controlled, cell-type-specific, and safety-conscious modulation of stress responses.
Congenital neutropenia (CN) is a heterogeneous group of inborn errors of immunity (IEI) characterized by defective neutrophil development and susceptibility to pyogenic infections. Constitutional neutropenia is a genetically heterogeneous group of disorders, and recent advances in genomic studies have revealed additional genetic causes associated with isolated or syndromic forms of neutropenia, including SMARCD2 deficiency. SMARCD2 is one of the implicated genes that encodes a component of the SWI/SNF chromatin-remodeling complex. Specific granule deficiency type 2 (SGD2) is an ultra-rare, syndromic, autosomal recessive form of CN caused by loss-of-function variants in SMARCD2. Only a small number of cases have been reported across the world to date. The clinical presentation of SGD2 is highly variable, ranging from isolated neutrophil defects to severe multisystem involvement. Here, we describe the twelfth patient diagnosed with a novel homozygous canonical splice site variant (c.1181_1181 + 3del) in the SMARCD2 gene (NM_001098426.2), and provide a comprehensive review of previously published cases to give a broad view of the clinical findings associated with the disease. Detailed characterization of SMARCD2-deficient patients and the underlying functional/molecular abnormalities will help to clarify the role of SMARCD2, particularly in immunity, and may ultimately lead to the development of more effective therapeutic approaches to reduce morbidity and improve quality of life in affected patients.
Inflammatory bowel disease is a chronic intestinal inflammation resulting from host-microbial interactions in genetically susceptible individuals. Two rat strains, Albino Oxford and Dark Agouti, differ in gut microbiota composition and the overall intensity of inflammatory responses. We investigated whether trinitrobenzenesulfonic acid-induced colitis in these two rat strains may be useful for studying therapies for colitis. Male Albino Oxford and Dark Agouti rats were treated intrarectally with trinitrobenzenesulfonic acid and monitored for 7 days. Colon tissue, peritoneal cavity and mesenteric lymph node cells were analysed for nitric oxide, urea and cytokine production, and peritoneal and lymph node cell phenotypes were determined by flow cytometry. Dark Agouti rats exhibited higher mortality following colitis induction than Albino Oxford rats, with longer segments of colonic necrosis/inflammation and a higher relative IL-17 A/IFN-γ balance in colon tissue and lymph node cells. Dark Agouti rats showed an increased proportion of neutrophils and a reduced proportion of macrophages in the peritoneal cavity, as well as a robust IL-6 response by peritoneal cavity cells. In contrast, Albino Oxford rats displayed a higher proportion of resident peritoneal cavity macrophages and lymphocytes in lymph nodes, and markedly increased production of IL-10 and urea by peritoneal cavity cells. The genetically determined inflammatory phenotype of Dark Agouti rats, in contrast to the less inflammatory character of Albino Oxford rats, may serve as a useful model for investigating therapies that target inflammatory processes in colitis. The use of rats with distinct inflammatory characteristics may help identify specific molecular targets in non-responsive individuals.
