American Journal of Pathology最新文献

Periostin deletion reduces corneal opacity and the infiltration of immune cells. 骨膜蛋白缺失可减少角膜混浊和免疫细胞浸润。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.007

Hyemin Seong, Chieun Song, Mingyo Kim, Woong-Sun Yoo, Mee-Young Choi, Réka Dorottya Varga, Yong-Ho Choe, Bina Lee, Seung Pil Yun, Young-Sik Yoo, Youngsub Eom, Choun-Ki Joo, Jinsung Yang, Seong-Jae Kim

{"title":"Periostin deletion reduces corneal opacity and the infiltration of immune cells.","authors":"Hyemin Seong, Chieun Song, Mingyo Kim, Woong-Sun Yoo, Mee-Young Choi, Réka Dorottya Varga, Yong-Ho Choe, Bina Lee, Seung Pil Yun, Young-Sik Yoo, Youngsub Eom, Choun-Ki Joo, Jinsung Yang, Seong-Jae Kim","doi":"10.1016/j.ajpath.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.007","url":null,"abstract":"Corneal opacity resulting from corneal injury is a leading cause of blindness. The interaction of extracellular matrix (ECM) proteins, cytokines and immune cells induces corneal opacity after corneal injury. Periostin, which is secreted into the ECM, is involved in wound healing and is associated with immune cell infiltration. The function of periostin in corneal wound healing and in the development of corneal opacity was investigated. Wild-type (WT) and Postn knockout (KO) mice underwent central corneal incision. Periostin expression level was significantly increased after the incision in WT mice, correlating with higher levels of wound healing markers, such as fibronectin and α-SMA, and increased corneal opacity. However, Postn KO mice showed reduced corneal opacity and immune cell infiltration, particularly from myeloid lineage cells after incision. Additionally, pro-inflammatory cytokine levels (IL-1β, IL-6, C1q) were not significantly changed in Postn KO mice. The results suggest that periostin deletion impairs corneal wound healing and reduces opacity by regulating cytokine expression and immune cell recruitment. The findings indicate that periostin can be a potential therapeutic target for reducing corneal opacity.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting RORγ to boost regulatory T cells and ameliorate diabetic retinopathy in mice. 靶向RORγ促进调节性T细胞和改善小鼠糖尿病视网膜病变。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.006

Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Abhirup Jayasimhan, Jennifer L Wilkinson-Berka

{"title":"Targeting RORγ to boost regulatory T cells and ameliorate diabetic retinopathy in mice.","authors":"Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Abhirup Jayasimhan, Jennifer L Wilkinson-Berka","doi":"10.1016/j.ajpath.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.006","url":null,"abstract":"Diabetic retinopathy, a leading cause of blindness, features damage to the retinal vasculature, where T cell-mediated inflammation is increasingly recognised as an important contributor. Retinoic acid receptor-related orphan receptor gamma (RORγ) plays a key role in regulating the balance between anti-inflammatory regulatory T cells (Tregs) expressing the transcription factor Foxp3 and pro-inflammatory Th17 cells. We hypothesised that inhibiting RORγ with SR2211, targeting both RORγ and its isoform RORγt, increases Tregs and reduces Th17 cells, resulting in reduced inflammation and vasculopathy in a streptozotocin-induced model of diabetic retinopathy. Mice expressing Foxp3 as a red fluorescent protein were treated with SR2211 for 26 weeks of diabetes, and comparisons made to diabetic mice administered vehicle and non-diabetic control mice. In blood and lymphoid tissues of diabetic mice, treatment with SR2211 restored the number of Tregs and reduced Th17 cells to the levels of diabetic mice + vehicle. In the retina of diabetic mice, treatment with SR2211 increased Tregs, and reduced the activation of microglia cells, the expression of pro-inflammatory factors including interleukin-17A, interleukin-6 and tumour necrosis factor, vascular leakage, vascular endothelial growth factor and acellular capillaries, compared to diabetic mice + vehicle. These findings indicate the ability of RORγ/RORγt inhibition to modulate specific T-cell responses and suppress microglia activation to reduce inflammation and vascular damage in diabetic retinopathy.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hepatocyte-specific MET deletion exacerbates acetaminophen-induced hepatotoxicity in mice. 肝细胞特异性MET缺失加剧对乙酰氨基酚诱导的小鼠肝毒性。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.010

Siddhi Jain, Ranjan Mukherjee, Gillian Williams, Jia-Jun Liu, Lanuza A P Faccioli, Zhiping Hu, Rodrigo M Florentino, George K Michalopoulos, Alejandro Soto-Gutierrez, Silvia Liu, Joseph Locker, Bharat Bhushan

{"title":"Hepatocyte-specific MET deletion exacerbates acetaminophen-induced hepatotoxicity in mice.","authors":"Siddhi Jain, Ranjan Mukherjee, Gillian Williams, Jia-Jun Liu, Lanuza A P Faccioli, Zhiping Hu, Rodrigo M Florentino, George K Michalopoulos, Alejandro Soto-Gutierrez, Silvia Liu, Joseph Locker, Bharat Bhushan","doi":"10.1016/j.ajpath.2025.09.010","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.010","url":null,"abstract":"Despite the well-known role of MET in liver regeneration following partial-hepatectomy (PHx), its role in the clinically-relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from PHx because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET-KO mice were given a toxic-dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated initial hepatotoxicity and consequentially impaired compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced JNK-activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative-damage, releasing cell-death inducer AIF into cytosol. Excess JNK-activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET-signaling. Pharmacological-activation of AKT reduced JNK-activation and hepatotoxicity in MET-KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling, but also activation of cell-death/senescence pathways along with impaired unfolded-protein-response in MET-KO mice. Analysis of published single-nucleus RNA-sequencing data showed proliferation in livers from APAP-induced ALF patients was associated with strong activation of HGF/MET signaling in hepatocytes, with spatial-transcriptomics showing striking induction of HGF surrounding the necrotic-zones. Interestingly, 35% of the genes altered in human-ALF were regulated by MET in the mouse AILI-model. In conclusion, present study demonstrates that MET is crucial for restraining hepatotoxicity following APAP overdose, via inhibiting mitochondrial cell-death signaling pathway.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The D2.B10-Dmd^mdx/J mouse model of DMD exhibits a severe mitochondrial deficiency not observed in the C57BL/10ScSn-Dmd^mdx/J mouse. D2。B10-Dmdmdx/J小鼠模型显示出C57BL/10ScSn-Dmdmdx/J小鼠未观察到的严重线粒体缺陷。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-30 DOI: 10.1016/j.ajpath.2025.09.005

Jennifer A Tinklenberg, Jessica Sutton, Rebecca A Slick, Hui Meng, Margaret Haberman, Mariah J Prom, Margaret J Beatka, Tatyana A Vetter, Audrey L Daugherty, Christina Pacak, J Patrick Gonzalez, Michael W Lawlor

{"title":"The D2.B10-Dmdmdx/J mouse model of DMD exhibits a severe mitochondrial deficiency not observed in the C57BL/10ScSn-Dmdmdx/J mouse.","authors":"Jennifer A Tinklenberg, Jessica Sutton, Rebecca A Slick, Hui Meng, Margaret Haberman, Mariah J Prom, Margaret J Beatka, Tatyana A Vetter, Audrey L Daugherty, Christina Pacak, J Patrick Gonzalez, Michael W Lawlor","doi":"10.1016/j.ajpath.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.09.005","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in dystrophin deficiency in skeletal/cardiac muscle and progressive loss of function. While the genetic causes of DMD have been thoroughly investigated, the energetic consequences have not been well examined across animal models. Previously, the lab examined mitochondrial function across nemaline myopathy mouse models of varying disease severity; here, mitochondrial phenotypes in DMD are assessed through the comparison of the milder C57BL/10ScSn-Dmdmdx/J (B10-mdx) and the more severe D2.B10-Dmdmdx/J mouse (D2-mdx) mouse models. D2-mdx exhibit a significant decrease in mitochondrial respiration, undetectable ATP concentrations, increased mitochondrial membrane potential, and alterations in electron transport chain enzyme activities. In contrast, B10-mdx show only mild mitochondrial phenotypes, including decreased ATP content. The D2-mdx mouse has genetic modifiers, including LTBP4 and ANXA6, that have been shown to alter DMD severity in humans. However, these modifiers did not account for mitochondrial differences seen in mdx mice. Both models were treated with a microdystrophin AAV gene therapy to assess whether dystrophin restoration rescued mitochondrial phenotypes. Gene therapy attenuated the ATP deficiency in the B10-mdx mice, but only improved mitochondrial membrane potentials in D2-mdx mice. The exact cause of the D2-mdx mitochondrial phenotypes remains unknown, but secondary disease processes that affect mitochondrial phenotypes should be taken into consideration when choosing an animal model for DMD studies.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Gut Microbiome as a Possible Mediator in Autoimmunity and Cardiovascular Disease: Shared Pathways and Therapeutic Implications. 肠道微生物群作为自身免疫和心血管疾病的可能中介：共享途径和治疗意义。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-26 DOI: 10.1016/j.ajpath.2025.08.015

Marina M Bellet, Francesco Curcio, Luigi Frati, Marilena Pariano, Luigina Romani, Massimiliano M Corsi-Romanelli

{"title":"The Gut Microbiome as a Possible Mediator in Autoimmunity and Cardiovascular Disease: Shared Pathways and Therapeutic Implications.","authors":"Marina M Bellet, Francesco Curcio, Luigi Frati, Marilena Pariano, Luigina Romani, Massimiliano M Corsi-Romanelli","doi":"10.1016/j.ajpath.2025.08.015","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.08.015","url":null,"abstract":"This review explores the emerging role of the gut microbiome in bridging autoimmunity and cardiovascular diseases (CVDs). Dysbiosis, an imbalance in gut microbial composition, disrupts immune regulation, metabolic pathways, and vascular health, likely contributing to both autoimmune disorders and CVDs. Microbial metabolites such as short-chain fatty acids, trimethylamine N-oxide, tryptophan derivatives, and bile acids play critical roles in modulating inflammation, lipid metabolism, and endothelial function. Specific bacterial species, including Faecalibacterium prausnitzii, Akkermansia muciniphila, and Bifidobacterium spp., exhibit dual protective effects against autoimmune and cardiovascular pathologies. By elucidating these interconnected mechanisms, this work highlights the potential of microbiome-targeted therapies, such as probiotics, prebiotics, and dietary interventions, to concurrently address autoimmune diseases and reduce cardiovascular risk. Understanding the complex interactions between the gut microbiota, immune system, and cardiovascular health opens new avenues for developing innovative therapeutic strategies aimed at restoring microbial balance and improving patient outcomes.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decreased Glycolysis due to LDHA m6A methylation in Endometrium of endometriosis impairs its decidualization and contributes to related infertility. 子宫内膜异位症患者因LDHA m6A甲基化导致糖酵解减少，损害其去个体化并导致相关不孕。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-26 DOI: 10.1016/j.ajpath.2025.08.016

Ruiweng Weng, Yi Liu, Wenqian Xiong

{"title":"Decreased Glycolysis due to LDHA m6A methylation in Endometrium of endometriosis impairs its decidualization and contributes to related infertility.","authors":"Ruiweng Weng, Yi Liu, Wenqian Xiong","doi":"10.1016/j.ajpath.2025.08.016","DOIUrl":"https://doi.org/10.1016/j.ajpath.2025.08.016","url":null,"abstract":"Endometriosis-related infertility is a prevalent reproductive health concern of global significance. Functional abnormalities of the endometrium are increasingly recognized as a pivotal contributor to infertility in affected individuals. In the present study, a significant reduction in glycolytic activity was observed in secretory-phase endometrial tissues obtained from patients with endometriosis, and this metabolic defect was attributed to downregulated expression of lactate dehydrogenase A (LDHA). This impaired glycolysis was found to induce defective endometrial decidualization and contribute to endometriosis-related infertility in a mouse model. Mechanistically, inhibition of LDHA promoted the production of reactive oxygen species (ROS) and apoptosis of endometrial stromal cells, ultimately resulting in compromised stromal cell decidualization. Furthermore, reduced LDHA expression was confirmed in the eutopic endometrium of patients with endometriosis, which was associated with decreased N6-methyladenosine (m6A) demethylation activity. This attenuation of m6A demethylation was, in turn, attributed to the downregulated expression of alkB homolog 5 (ALKBH5)-a key enzyme responsible for m6A demethylation modification. Collectively, our findings demonstrate that elevated m6A methylation levels in the eutopic endometrium of patients with endometriosis impair endometrial glycolytic metabolism and decidualization of endometrial stromal cells, thereby contributing to endometriosis-related infertility. This pathological cascade is mediated by the downregulation of LDHA expression.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retraction Notice to “Aberrant CD8+ T-Cell Responses and Memory Differentiation upon Viral Infection of an Ataxia-Telangiectasia Mouse Model Driven by Hyper-Activated Akt and mTORC1 Signaling” [Am J Pathol 178 (2011) 2740–2751] “超激活Akt和mTORC1信号驱动的异常CD8+ t细胞反应和记忆分化对ataxi -毛细血管扩张小鼠模型的影响”[J] .中华病理学杂志，2011(11):2740-2751。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-23 DOI: 10.1016/j.ajpath.2025.08.002

Anthony D. D’Souza , Ian A. Parish , Sharen E. McKay , Susan M. Kaech , Gerald S. Shadel

引用次数: 0

From The American Journal of Pathology's Archives 摘自《美国病理学杂志档案》

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-23 DOI: 10.1016/j.ajpath.2025.02.011

Chris Albanese, Olga C. Rodriguez

引用次数: 0

Stromal Steroid 5 α-Reductase Type 2 Promotes Prostate Growth through WNT5A-Lymphoid Enhancer-Binding Factor 1-Insulin-Like Growth Factor 1 Signaling in Benign Prostatic Hyperplasia. 在良性前列腺增生中，基质SRD5A2通过WNT5A-LEF1-IGF1信号通路促进前列腺生长。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-12 DOI: 10.1016/j.ajpath.2025.08.011

Christina Sharkey, Boqing Gu, Xingbo Long, Yao Tang, Nicolas Patsatzis, Steven Li, Aria F Olumi, Zongwei Wang

{"title":"Stromal Steroid 5 α-Reductase Type 2 Promotes Prostate Growth through WNT5A-Lymphoid Enhancer-Binding Factor 1-Insulin-Like Growth Factor 1 Signaling in Benign Prostatic Hyperplasia.","authors":"Christina Sharkey, Boqing Gu, Xingbo Long, Yao Tang, Nicolas Patsatzis, Steven Li, Aria F Olumi, Zongwei Wang","doi":"10.1016/j.ajpath.2025.08.011","DOIUrl":"10.1016/j.ajpath.2025.08.011","url":null,"abstract":"Steroid 5 α-reductase type 2 (SRD5A2) is a key enzyme in androgen metabolism and a pharmacologic target in benign prostatic hyperplasia. Although SRD5A2 is known to mediate stromal-epithelial interactions that influence prostate growth, the relationship between baseline SRD5A2 expression and prostate volume remains unclear. In this study, SRD5A2 expression was analyzed in human prostate tissues from the Medical Therapy of Prostatic Symptoms trial and institutional biorepository cohorts. Quantitative assessments were performed and correlations were evaluated between expression level of SRD5A2, WNT5A, prostate volume, and tissue signaling profiles. SRD5A2 expression was significantly associated with total prostate and transition zone volume. Stromal-specific WNT5A expression showed a strong positive correlation with SRD5A2, whereas neither serum nor tissue dihydrotestosterone levels correlated with SRD5A2 expression. In Srd5a2-null mice, Wnt5a expression in the prostate stroma was dependent on Srd5a2 and showed region-specific regulation. Mechanistically, SRD5A2 overexpression in human prostate stromal cells up-regulated WNT5A and lymphoid enhancer-binding factor 1, activated insulin-like growth factor 1 (IGF1) signaling, increased proliferation, and reduced apoptosis. Conditioned media from these cells enhanced epithelial proliferation through paracrine IGF1 activity. This study provides the first evidence that SRD5A2 promotes prostate growth through a stromal WNT5A-lymphoid enhancer-binding factor 1-IGF1 paracrine signaling axis independent of androgen levels, suggesting a novel therapeutic mechanism relevant for patients with benign prostatic hyperplasia with resistance to conventional 5 α-reductase inhibitor therapy.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Low Potassium Triggers Tubular Epithelial NLR Family Pyrin Domain-Containing 3/Apoptosis-Associated Speck-Like Protein-Containing CARD-Driven Kidney Inflammation Independently of Inflammasomes. 低钾触发小管上皮NLRP3/ asc驱动的肾脏炎症，独立于炎症小体。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2025-09-12 DOI: 10.1016/j.ajpath.2025.08.010

Satoko Komori, Takanori Komada, Takayoshi Matsumura, Tadayoshi Karasawa, Yutaka Miura, Chintogtokh Baatarjav, Yoshitaka Gunji, Hidetoshi Aizawa, Yoshiko Mizushina, Noriyoshi Fukushima, Toru Sugihara, Satoshi Ando, Tetsuya Fujimura, Daisuke Nagata, Masafumi Takahashi

{"title":"Low Potassium Triggers Tubular Epithelial NLR Family Pyrin Domain-Containing 3/Apoptosis-Associated Speck-Like Protein-Containing CARD-Driven Kidney Inflammation Independently of Inflammasomes.","authors":"Satoko Komori, Takanori Komada, Takayoshi Matsumura, Tadayoshi Karasawa, Yutaka Miura, Chintogtokh Baatarjav, Yoshitaka Gunji, Hidetoshi Aizawa, Yoshiko Mizushina, Noriyoshi Fukushima, Toru Sugihara, Satoshi Ando, Tetsuya Fujimura, Daisuke Nagata, Masafumi Takahashi","doi":"10.1016/j.ajpath.2025.08.010","DOIUrl":"10.1016/j.ajpath.2025.08.010","url":null,"abstract":"Pathologic potassium (K+) deficiency causes kidney inflammation and injury, known as hypokalemic nephropathy (HN), the underlying pathogenesis of which is obscure. NLR family pyrin domain-containing 3 (NLRP3) inflammasomes are platforms that sense the reduction of intracellular K+, engaging inflammation and tissue injury. The present study investigated whether or not systemic K+ deficiency induces NLRP3 inflammasome activation in HN. Clinically diagnosed HN in humans manifested up-regulation of NLRP3 and apoptosis-associated speck-like protein-containing CARD (ASC) in the kidney epithelia. A K+ depletion model in mice demonstrated that kidney-resident NLRP3 and ASC play key roles in triggering early inflammation in HN kidneys. Unexpectedly, the K+ depletion-induced kidney inflammation was not dependent on inflammasome activation. A single-cell RNA-sequencing analysis revealed ASC up-regulation, NF-κB activation, and an increased level of tumor necrosis factor-like weak inducer of apoptosis receptor FN14 in the HN kidneys, primarily in the distal nephron/collecting duct epithelial cells. Although kidney epithelial cells did not drive NLRP3 inflammasomes, NLRP3 and ASC alternatively enhanced with-no-lysine kinase-dependent NF-κB signaling in response to tumor necrosis factor-like weak inducer of apoptosis under a low-K+ milieu. These findings indicate a unique proinflammatory cascade mediated by NLRP3 and ASC beyond the framework of inflammasomes, which broadens the understanding of electrolyte-associated immunity in the kidney.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0