American Journal of Pathology最新文献

Stimulator of interferon genes (STING), an effector protein anchored in the endoplasmic reticulum, translocates to Golgi upon activation. Canonically recognized for its central function in innate immune defense against cytosolic endogenous or exogenous double-stranded DNA from damaged host cells or pathogens, STING is now known to have noncanonical functions beyond innate immune surveillance. These novel noncanonical functions of STING include modulating autophagy, maintaining endoplasmic reticulum and mitochondrial calcium homeostasis, interacting with endoplasmic reticulum stress sensor protein, and regulating Golgi proton efflux and integrity of the secretory pathway. Recent research in murine models has linked aberrant STING activation to kidney disorders, including acute kidney injury, podocytopathies, chronic kidney disease, apolipoprotein L1-mediated kidney disease, autosomal dominant polycystic kidney disease, and autosomal dominant tubulointerstitial kidney disease. This review summarizes the diverse functions of STING in addition to interferon signaling, highlighting its emerging importance in the pathogenesis of kidney disease and underscoring its promise as a drug target.

Hypoxia-inducible factor-1α (HIF-1α) is associated with myopia, but the underlying mechanisms remain unclear. This study investigates the role of HIF-1α in ocular refractive development and its mechanisms. Sprague-Dawley rats were induced with myopia using the form deprivation method, and the expression of HIF-1α was analyzed by Western blot analysis. Oxidative stress levels were assessed by measuring reactive oxygen species, superoxide dismutase, and malondialdehyde. Additionally, the protein expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11/xCT) was evaluated using Western blot analysis and immunohistochemistry, and extracellular matrix remodeling was assessed by measuring matrix metalloproteinase 2 (MMP2), tissue inhibitor of MMP2 (TIMP2), α-smooth muscle actin (α-SMA), and collagen 1α1 (COL1A1). Results showed that HIF-1α expression was significantly up-regulated in form deprivation-induced myopic rats, with increased levels of oxidative stress and ferroptosis. In fibroblast cells under low oxygen conditions, MMP2 and α-SMA levels increased, whereas TIMP2 and COL1A1 levels decreased. Transfection with shRNA targeting HIF1A (sh-HIF1A) lentivirus elevated GPX4 and xCT expression, and HIF-1α knockdown reduced MMP2 and α-SMA expression while increasing TIMP2 and COL1A1 expression. However, erastin restored their levels. Furthermore, DNA methyltransferase 3A suppressed HIF-1α expression by promoting its promoter methylation. In conclusion, hypoxia-induced HIF-1α expression promotes ferroptosis and extracellular matrix remodeling, contributing to the pathogenesis of myopia. DNA methyltransferase 3A may reduce HIF-1α expression through methylation, positioning it as a potential target for myopia therapy.

Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by glycogen branching enzyme (GBE1) deficiency, resulting in the accumulation of insoluble polyglucosan. The Gbe1^ys/ys mouse model, carrying the p.Y329S variant, recapitulates features of adult-onset GSD IV, also known as adult polyglucosan body disease. However, the natural progression of the disease in this model is not fully understood. This study presents a longitudinal analysis of Gbe1^ys/ys mice from 1 to 12 months of age, quantitatively tracking polyglucosan accumulation and correlating it with progressive histopathologic, motor, and behavioral changes. Polyglucosan bodies were detected as early as 1 month, with significant neurodegeneration and astrogliosis by 6 months. Notably, serum neurofilament light chain levels increased with disease progression, identifying neurofilament light chain as a potential noninvasive biomarker of neurodegeneration in GSD IV. Systemic involvement, including severe splenomegaly and gastrointestinal abnormalities, indicates broader effects of GBE1 deficiency beyond the central nervous system. These findings provide important insights into the natural history of GSD IV, establish key disease milestones for therapeutic intervention, and refine the clinical understanding of GSD IV and adult polyglucosan body disease.

Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents. Unfortunately, many people experience negative adverse effects associated with long term GC therapy, developing GC-induced ocular hypertension (GC-OHT), which can lead to secondary glaucoma. Approximately 40% of the treated individuals are susceptible to GC-OHT. Seventy years since this discovery, the molecular mechanisms underlying GC-OHT remain unclear. We previously developed a mouse model of GC-OHT delivering the potent GC dexamethasone and observed strain-specific disparities in the development of GC-OHT. We now compare phenotypic and transcriptomic differences between five genetically distinct inbred mouse strains to identify biomarkers of GC susceptibility, and to better understand the molecular mechanisms of GC-OHT. Like humans, mouse strains differ in their ability to develop GC-OHT. Phenotypic characterization revealed that C57BL/6J and C3H/HeJ mice are GC responders and more susceptible to develop GC-OHT. Dexamethasone treatment in these strains led to elevated intraocular pressure compared with the GC nonresponder strains DBA/2J.Gpnmb⁺, 129P3/J, and BALB/cJ. Transcriptomic analysis of responder and nonresponder mouse strains revealed novel trabecular meshwork biomarkers of GC-OHT susceptibility involving enrichment of molecular pathways unique to this response. The present study identifies putative mechanisms underlying GC-OHT and provides insight into the pathogenesis of the clinically similar but more prevalent primary open-angle glaucoma.

Deep learning (DL) models have shown promise in predicting molecular alterations directly from hematoxylin and eosin-stained whole slide images in a variety of solid tumors, offering a rapid alternative to conventional molecular testing. However, these models often offer limited insight into their decision-making process, undermining transparency and eroding clinical trust. Interpreting model predictions is essential for a meaningful application of DL in clinical pathology. This is showcased by interpreting the outputs of a weakly supervised DL model, XpressO-melanoma, that predicts BRAF V600E mutation status from whole slide images of skin cutaneous melanoma. The morphologic plausibility of the model's segmentations of the tumor regions of interest and their prediction of BRAF V600E status were evaluated and compared against the pathologists' annotations for the same. The work resulted into four interpretation categories that associate model's performance (ie, area under the curve of 0.8 and precision and recall of 0.7) with the regions of interest that revealed meaningful diagnostic patterns as well as those that required annotation refinements. The work coheres with the White House's National AI [Artificial Intelligence] Action Plan that identifies interpretability as a national research priority and paves the way for a human-DL collaboration in clinical pathology for a better translation of DL techniques in clinical pathology in the near future.

Psoriasis is a chronic, immune-mediated inflammatory disorder characterized by keratinocyte hyperproliferation and systemic immune dysregulation. The neuroimmune axis, linking sensory nerve activity, neuropeptide signaling, and immune responses, is central to disease pathogenesis. Structural remodeling of sensory nerves enhances the release of neuropeptides such as Substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y, which activate dendritic cells, promote T-cell proliferation, and stimulate keratinocyte cytokine production, sustaining a neurogenic inflammatory loop. Psychological stress exacerbates inflammation through hypothalamic-pituitary-adrenal (HPA) axis dysregulation, altering cortisol signaling and systemic immune responses. Intracellular pathways, including mitogen-activated protein kinase, PI3KAktmTOR, JAKSTAT, and NF-κB, along with epigenetic modifications, integrate neural and immune signals, contributing to disease chronicity and heterogeneity. Targeting neuroimmune interactions through neuropeptide antagonists, neuromodulation, stress management, and precision immunotherapies reduces cutaneous inflammation and addresses systemic comorbidities. This review synthesizes molecular, cellular, and clinical insights into the neuroimmune-HPA axis network in psoriasis, highlighting its therapeutic potential for personalized and multidisciplinary management.

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder with progressive myofiber degeneration and fibrosis from dystrophin deficiency. Current therapies are largely supportive with limited anti-fibrotic benefit, prompting new strategies. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. Open-access proteomic and transcriptomic data sets were integrated for in silico analyses, including differential gene expression, weighted gene co-expression network analysis, and pathway enrichment, to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine data sets. Therapeutic effects were tested with empagliflozin (EMPA) in mdx mice (30 mg/kg per day for 4 weeks, starting at 12 weeks) and DMD^mdx rats (10 mg/kg per day for 4 months, starting at 5 months), with vehicle controls. Validation used quantitative RT-PCR, grip-strength testing, and histologic fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included COL3A1, COL5A2, and TGFB1. EMPA reduced Tgfb1 expression in DMD rats and significantly decreased collagen deposition in skeletal muscle. Functional testing showed longer grip duration in EMPA-treated mice. Immune profiling revealed shifts in T cells and macrophages, indicating immunomodulation. Findings were consistent across species and data modalities analyzed. These results demonstrate that EMPA modulates fibrosis, inflammation, and muscle endurance in DMD models. These data support repurposing SGLT2i as a promising therapeutic strategy for DMD.

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), essential for HA degradation, has been reported to promote endochondral ossification in developing bone but to inhibit intramembranous ossification. However, little is known about the role of HYBID in long bone fracture healing, which requires both types of ossification. The role of genetic Hybid depletion in healing was examined in a murine model of femoral diaphyseal fracture. On micro-computed tomography, bridging of fracture gaps was delayed in Hybid-deficient (Hybid^-/-) mice compared to wild-type mice. On histologic analysis, the resorption of cartilaginous callus was retarded due to decreased osteoclasts/chondroclasts and blood vessels at the chondro-osseous junction of cartilaginous and bony callus in Hybid deficiency, with delayed fusion of fracture gaps. At 2 weeks after fracture, Hybid was highly expressed by osteoblasts and hypertrophic chondrocytes in callus of wild-type mice, and Il-6 was overexpressed at 1 week, followed by transforming growth factor β₁ and bone morphogenic protein 2 expression at 2 and 3 weeks. High-molecular-weight HA accumulated in the callus tissue of the Hybid^-/- mice. In both groups, fracture healing was promoted with injections of low-molecular-weight HA around the calluses of the fractured femora. These data suggest that fracture healing is delayed in HYBID deficiency due to impaired endochondral ossification, and that HYBID-mediated HA depolymerization is involved in bone fracture healing.

Angiopoietin-like 4 (Angptl4) is a secreted glycoprotein involved in the regulation of various homeostatic and disease processes. In the intestine, prior studies have suggested protective roles for Angptl4 in inflammation using Angptl4 knockout mouse models; however, phenotypic variability-such as perinatal lethality and intestinal inflammation accompanied by lymphatic defects in only a subset of animals-has complicated the interpretation of its role in intestinal pathogenesis. In this study, the impact of Angptl4 deficiency was examined using a subset of Angptl4 knockout mice that survive postnatally without overt abnormalities. It was found that loss of Angptl4 confers protection against colitis and colitis-associated colorectal tumorigenesis. These protective effects were associated with the alternative activation of anti-inflammatory M2-like macrophages. Similarly, in a genetic model of intestinal tumorigenesis, Angptl4 deficiency resulted in reduced tumor burden and attenuated inflammation, accompanied by increased M2-like macrophages. Analysis of human colorectal cancer data sets further revealed that low ANGPTL4 expression is associated with improved survival outcomes as well as reduced expression of inflammation-related marker genes. Collectively, the findings uncover a previously unrecognized protective effect of Angptl4 deficiency against intestinal pathogenesis via anti-inflammatory mechanisms, suggesting Angptl4 as a potential therapeutic target and prognostic biomarker for colorectal cancer and inflammatory bowel disease.

Pediatric cholestatic liver diseases are rare but serious conditions that frequently progress to liver fibrosis and cirrhosis and often require transplantation. Despite the clinical importance of these diseases, the mechanisms driving disease progression remain poorly understood. Hepatic iron accumulation was identified as a pathologic feature associated with congenital cholestatic liver disease in mice with a liver-specific deletion of Yap, a gene critical for bile duct development. Further hepatic iron overload induced by liver-specific deletion of Fbxl5, a key regulator of cellular iron homeostasis, exacerbated cholestatic liver injury and fibrosis in Yap-deficient mice. Mechanistically, iron overload enhanced the susceptibility to bile acid-induced cytotoxicity via ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation. This ferroptotic process was confirmed by the suppression of bile acid-induced cell death through iron chelation and lipid peroxide scavenging in ex vivo liver slice cultures. Furthermore, both dietary iron restriction and antioxidant treatment mitigated liver injury in vivo. These findings identify iron accumulation as a key driver of disease progression and highlight iron metabolism and ferroptosis as potential therapeutic targets in congenital cholestatic liver disease.