Inflammation Research最新文献

{"title":"A platelet-monocyte pyroptotic axis mediates uremic cardiomyopathy: critical role of PF4 and hematopoietic caspase-1.","authors":"Yang Yang, Minyu Zhang, Meihan Chen, Xiaomeng Li, Jing Xu, Ti Zhang, Dongjuan Zhang, Deyang Kong, Lu Ma, Ai Peng, Changlin Mei","doi":"10.1007/s00011-026-02311-9","DOIUrl":"10.1007/s00011-026-02311-9","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD). While platelet activation and monocyte inflammation are hallmarks of uremia, how platelet-derived factors drive monocyte-mediated cardiac remodeling remains elusive. We investigated the role of platelet factor-4 (PF4) in monocyte pyroptosis and its contribution to uremic cardiomyopathy.</p><p><strong>Methods: </strong>A uremic mouse model was established by 5/6 nephrectomy (Nx). Differentially expressed genes between Ly6C⁺ and Ly6C⁻ monocyte subsets were identified by microarray and WGCNA. PF4 effects were assessed by systemic administration with or without CXCR3 inhibition or PF4 neutralization. Caspase-1 activation was evaluated by FAM-FLICA staining and IL-1β ELISA. The role of caspase-1 was examined using global Casp1^⁻/⁻ mice and bone marrow (BM) transfer experiments.</p><p><strong>Results: </strong>In uremic mice, circulating Ly6C⁺ monocytes decreased time-dependently. Bioinformatics identified Pf4 as a key hub gene, with six pyroptosis-associated genes upregulated in Ly6C⁺ monocytes versus sham controls. PF4 infusion, at least in part through CXCR3, shortened Ly6C⁺ monocyte lifespan, upregulated pyroptosis-related genes, increased active caspase-1⁺ cells and IL-1β release, and accelerated cardiac dysfunction and fibrosis. CXCR3 inhibition or PF4 neutralization attenuated these effects. Global Casp1 knockout, which retained intact Casp11 expression, protected mice from PF4-exacerbated cardiac injury. BM transplantation from Casp1^⁻/⁻ into wild-type mice conferred the same protective phenotype, identifying BM-derived caspase-1 as a key driver.</p><p><strong>Conclusion: </strong>Our study identifies a pathway where PF4, acting partly through CXCR3, contributes to caspase-1-dependent pyroptosis in Ly6C⁺ monocytes, driving pathological cardiac remodeling in uremia. Targeting this axis in BM-derived cells may represent a therapeutic strategy for heart failure in ESRD.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomic analysis identifies a MIF-driven keratinocyte-macrophage-Th2 axis as a key inflammatory circuit in atopic dermatitis.","authors":"Yan Wei, Rui-Min Bai, Hao-Ran Guo, Jin Shan, Li-Juan Wang, Yan Zhou, Kuan-Hou Mou, Yan Zheng, Ya-Guang Zhang","doi":"10.1007/s00011-026-02316-4","DOIUrl":"10.1007/s00011-026-02316-4","url":null,"abstract":"<p><strong>Background: </strong>Atopic dermatitis (AD) is a chronic inflammatory skin disorder involving complex interactions among multiple cell types. The cellular heterogeneity and intercellular communication networks driving AD pathogenesis remain to be fully elucidated.</p><p><strong>Methods: </strong>Single-cell RNA sequencing datasets were employed to identify cell types in lesional skin of AD patients and analyze the transcriptomic characteristics of keratinocytes, T cells, and macrophages. Cell clusters were identified based on marker gene expression, and intercellular communication networks were analyzed to investigate cell-cell interactions. The findings were validated using in vitro cell models (HaCaT, HEK, primary keratinocytes, and THP-1 cells) and an MC903-induced AD mouse model, with MIF expression assessed by qPCR and Luminex. Immunofluorescence staining was used to evaluate the distribution and aggregation of macrophages. Functional studies were conducted using MIF098 to inhibit MIF signaling.</p><p><strong>Results: </strong>scRNA-seq revealed significant cellular remodeling in AD lesions, with marked enrichment of keratinocytes, T cells, and macrophages. The proportion of Th2 cells was increased in AD lesion tissues, and an MRC1⁺ macrophage subset (Cluster3-Mac) was specifically enriched in AD lesions. Intercellular communication analysis demonstrated that proliferative keratinocytes may interact with Cluster3-Macrophages via the MIF-CD74/CD44 signaling axis, with proliferative keratinocytes acting as senders and macrophages as receivers. Furthermore, MRC1⁺ macrophages may engage with Th2 cells through PTPRC. Consistent with these findings, MIF expression was significantly upregulated in the serum of AD patients, in IL-13-treated HaCaT and HEK cells, and in the epithelial tissues of AD model mice. In the MC903-induced AD mouse model, lesional skin showed epidermal thickening, inflammatory infiltration, and accumulation of M2-polarized macrophages (F4/80⁺CD206⁺). Functional validation using MIF098 showed that inhibition of MIF downregulated its expression in primary keratinocytes and reduced the ability of THP-1 cells to secrete CCL17, CCL22, and IL-10.</p><p><strong>Conclusion: </strong>Our findings identify a critical role for the MIF signaling axis in mediating crosstalk between proliferative keratinocytes and M2-polarized macrophages, thereby promoting Th2-driven inflammation in AD. Targeting MIF may represent a potential therapeutic strategy for AD.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Agmatine induces mitophagy via the PTS-I2R pathway to increase autophagic flux and attenuate sepsis-induced intestinal epithelial cell apoptosis.","authors":"He Jin, Shuangqin Yin, Yongming Li, Xiangwei Hou, Lin Qiao, Tianyin Kuang, Jing Zhou, Xue Yang, Wanting Zeng, Chao Fan, Li Luo, Lihui Wang, Hongyan Xiao, Shengxiang Ao, Shan Su, Quanwei Bao, Yibin Ouyang, Huaping Liang, Junyu Zhu","doi":"10.1007/s00011-026-02314-6","DOIUrl":"10.1007/s00011-026-02314-6","url":null,"abstract":"<p><strong>Background: </strong>The therapeutic options for sepsis-induced intestinal injury, which drives multiple organ dysfunction and mortality, are limited, but the role of polyamine supplements remains unclear. This study aimed to elucidate the protective effect of agmatine (AGM) on sepsis-induced intestinal injury and its mitochondrial-targeted antiapoptotic mechanism in intestinal epithelial cells (IECs).</p><p><strong>Methods: </strong>We verified the transport and subcellular localization of AGM in IECs via fluorescence assays and established in vitro and in vivo IEC apoptosis models. Functional evaluations using cell viability assays, laser confocal imaging, flow cytometry, transmission electron microscopy, and multiomics techniques were performed.</p><p><strong>Results: </strong>AGM attenuated sepsis-induced intestinal injury, as evidenced by its ability to lower the serum levels of intestinal damage markers in septic mice, attenuate inflammatory factor production and pathological damage in the intestine, and reduce IEC apoptosis. AGM entered IECs via the polyamine transport system (PTS), but not the NMDA receptor, and inhibited IEC apoptosis induced by TNFα/CHX or TNFα/ActD. Notably, AGM exerted its antiapoptotic effect by targeting the mitochondrial imidazoline I2 receptor (I2R). Mechanistically, AGM induced mitophagy by decreasing the mitochondrial membrane potential without altering mitochondrial number or function, as ROS production, calcium ion influx, ATP generation, and oxygen consumption were unchanged. AGM also increased autophagic flux, as confirmed upon treatment with various autophagy inhibitors.</p><p><strong>Conclusion: </strong>AGM alleviates sepsis-induced intestinal injury via the PTS-I2R axis by promoting mitophagy and autophagic flux to inhibit IEC apoptosis, laying a foundation for the use of AGM as a potential nutritional supplement or therapeutic agent for sepsis-induced intestinal injury.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spleen-associated macrophage alterations and embryo viability in a murine model of recurrent spontaneous abortion.","authors":"Kang Zhu, Hailong Zhang, Sijia Chen, Xi Deng, Xi Chen, Dan Wan, Mengchen Zhu, Chen Zhang, Yane Gao","doi":"10.1007/s00011-026-02323-5","DOIUrl":"10.1007/s00011-026-02323-5","url":null,"abstract":"<p><strong>Background: </strong>Recurrent spontaneous abortion (RSA) is commonly attributed to immune dysregulation at the maternal-fetal interface. The contribution of the spleen, as a peripheral immune organ, remains unclear. This study investigated spleen-associated immune alterations in a murine model of RSA.</p><p><strong>Methods: </strong>An RSA model was established by mating CBA/J females with DBA/2 males. Splenic and decidual immune-cell distributions were assessed by histology, flow cytometry, and cytokine analysis. Splenectomy and macrophage depletion were performed as experimental interventions. Decidual transcriptomic changes following splenectomy were analyzed by bulk RNA sequencing and transcriptomic enrichment analyses.</p><p><strong>Results: </strong>RSA mice exhibited splenomegaly, altered splenic histological features, and changes in splenic immune-cell composition, including increased numbers of Ly6C⁺ CX3CR1^lo macrophages. Decidual immune alterations mirrored several changes observed in the spleen. Splenectomy was associated with increased embryo viability, reduced histological alterations, and changes in decidual immune-cell distributions. Similar effects on embryo viability and decidual immune-cell distributions were observed following effective macrophage depletion. Transcriptomic analyses of decidual tissue following splenectomy identified transcriptional differences involving mitochondrial-associated, Wnt-related, and protein synthesis-associated pathways.</p><p><strong>Conclusion: </strong>These findings identify an association between spleen-associated immune alterations and RSA and suggest that splenectomy is accompanied by changes in decidual immune-cell distributions, tissue-level transcriptional patterns, and embryo viability.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic intermittent hypoxia sustains the low-grade inflammatory memory of monocytes via activation of myelopoiesis.","authors":"Shi Qi Li, Yi Wang, Meng Yao Li, Liu Zhang, Xi Xi Chen, Ying Ni Lin, Li Na Zhou, Xian Wen Sun, Yong Jie Ding, Qing Yun Li","doi":"10.1007/s00011-026-02321-7","DOIUrl":"10.1007/s00011-026-02321-7","url":null,"abstract":"<p><strong>Objective: </strong>Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), drives a chronic low-grade inflammatory state linked to multiple comorbidities. Monocytes play a pivotal role in the regulation of inflammatory responses. This study aimed to characterize the inflammatory profile of monocytes induced by CIH.</p><p><strong>Methods: </strong>Distribution and activation status of monocytes were analyzed in OSA versus healthy controls. In vivo, models of CIH were employed to assess the immediate and long-term effects on monocyte inflammatory profiles and bone marrow (BM) myelopoiesis.</p><p><strong>Results: </strong>Monocytes derived from OSA patients exhibited enhanced activation marker expression and cytokine secretion. In vivo, CIH provoked immediate inflammatory responses of peripheral monocytes, accompanied by increased abundance of hematopoietic stem and progenitor cells in the BM, resulting in enhanced myelopoiesis and increased circulating monocytes. After normoxic recovery, monocytes from CIH-exposed mice exhibited heightened inflammatory responses upon secondary challenge, which was associated with sustained, myeloid-biased myelopoiesis in the BM.</p><p><strong>Conclusions: </strong>Our findings demonstrate that CIH sustains a low-grade inflammatory memory in monocytes, characterized by both basal activation and enhanced responsiveness to secondary stimulation. We identify the establishment of maladaptive myelopoiesis as a novel mechanism for the sustained inflammatory state in OSA, providing new insights into the pathogenesis of inflammatory responses and comorbidities associated with OSA.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell profiling reveals clonal CD8⁺T cell-derived IFNγ drives Sjögren's disease-related dacryoadenitis.","authors":"Hao-Xian Zhu, Fang-Fang Li, Xiao-Min Chen, Bing-Yang Zhang, Ting Xu, Zhe-Xiong Lian, Cai-Yue Gao, Qian-Li Meng","doi":"10.1007/s00011-026-02322-6","DOIUrl":"10.1007/s00011-026-02322-6","url":null,"abstract":"<p><strong>Background: </strong>Sjögren's disease (SjD) is a chronic progressive autoimmune disorder primarily affecting the exocrine glands. Dacryoadenitis represents one of the typical clinical manifestations of SjD, yet its underlying pathogenic mechanisms remain poorly understood. This study investigated the immune microenvironment of the lacrimal gland to elucidate the pathogenic cell subset and key molecular factors driving SjD-related dacryoadenitis.</p><p><strong>Methods: </strong>Aire^-/- mice, a well-established SjD-related dacryoadenitis model, were employed in this study. Lacrimal gland infiltrating immune cells were profiled by single-cell RNA sequencing and flow cytometry. The T-cell repertoire of lacrimal gland T cells was characterized by single-cell T cell receptor (TCR) sequencing. Ifng^-/-Aire^-/- mice were used to evaluate the roles of IFNγ in SjD-related dacryoadenitis model. The immunologic profiles and histopathological changes of the lacrimal gland were assessed in Aire^-/- mice with or without IFNγ deficiency.</p><p><strong>Results: </strong>We identified a clonally expanded population of CCL5⁺CD8⁺ memory T cells with high expression of cytotoxic effector molecules that is in spatial proximity to acinar cells. IFNγ derived from CCL5⁺CD8⁺memory T cells acts on multiple cell types, upregulating costimulatory molecules and chemokines within the lacrimal gland. Notably, either CD8⁺ T cell deletion or IFNγ knockout resulted in a marked attenuation of inflammatory infiltration and acinar atrophy within the lacrimal glands of Aire^-/- mice.</p><p><strong>Conclusions: </strong>IFNγ derived from clonally expanded CCL5⁺CD8⁺memory T cells drives the pathogenesis of SjD-related dacryoadenitis, supporting IFNγ blockade as a potential therapeutic strategy for SjD-related dacryoadenitis.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From acute mast cell activation to a structured immunothrombotic and autoimmune niche in chronic spontaneous urticaria.","authors":"Paulo Ricardo Criado, Roberta Fachini Jardim Criado, Beatrice Martinez Zugaib Abdalla","doi":"10.1007/s00011-026-02320-8","DOIUrl":"10.1007/s00011-026-02320-8","url":null,"abstract":"<p><strong>Background: </strong>Chronic spontaneous urticaria (CSU) presents recurrent wheals and/or angioedema for more than six weeks without an identifiable trigger. Although mast cell activation and histamine release are well-established effector mechanisms, this model does not explain disease persistence, immune dysregulation, or treatment refractoriness. A deeper mechanistic framework is required to explain progression to chronic disease.</p><p><strong>Purpose: </strong>To propose a stage-wise CSU chronification model, reframing the disease as a structured dermal immunothrombotic and autoimmune niche rather than an episodic mast cell-effector event, and to derive therapeutic implications.</p><p><strong>Methods: </strong>A narrative synthesis of ultrastructural, immunohistochemical, transcriptomic, and clinical evidence from the published clinical literature, including original studies from our group on acute drug-induced urticaria and antihistamine-refractory CSU was performed.</p><p><strong>Results: </strong>Five sequential stages drive chronification: (1) FcεRI/BTK-dependent mast cell degranulation; (2) eosinophil tissue-factor activation of the coagulation-complement loop; (3) FXIIIa⁺ dendrocyte phagocytosis and T-cell priming via OX40/OX40L; (4) Th2-driven M2 macrophage polarization with autoantibody-mediated mast cell reactivation; and (5) JAK/STAT and IFN-λ1 signaling sustaining dermal immune niche. Transcriptomic hub genes and cytokine profiling further support this model.</p><p><strong>Conclusion: </strong>CSU reflects a structured immune architecture rather than isolated mast cell activation. This explains treatment refractoriness and supports targeting upstream checkpoints, including BTK, JAK, and OX40/OX40L for sustained control.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipopolysaccharide promotes rheumatoid arthritis by enhancing Wnt7b mediated macrophage-FLS communication.","authors":"Bing Wang, Yingqiu Song, Wenbo Xu, Jiaqing Chen, Yurong Huang, Xinyue Zhou, Yikang Cai, Aixin Xia, Yanping Li, Liwei Jiang, Faxue Liao, Jian Huang, Chenggui Miao","doi":"10.1007/s00011-026-02318-2","DOIUrl":"10.1007/s00011-026-02318-2","url":null,"abstract":"<p><strong>Background: </strong>Our previous research has shown that lipopolysaccharide (LPS) derived from Gram-negative bacteria in the intestine promoted rheumatoid arthritis (RA) after entering peripheral blood, but the specific molecular mechanism was unclear.</p><p><strong>Method: </strong>This study used transcriptome and proteomic sequencing, western blotting, co-immunoprecipitation (Co-IP), cell co-culture, and other related methods to investigate whether LPS entering peripheral blood activated the Wnt7b secretion in macrophages, and used the Wnt7b as a messenger molecule to promote the communication between macrophage-fibroblast-like synoviocyte (FLSs), ultimately leading to the onset of RA.</p><p><strong>Result: </strong>The results showed that LPS significantly promoted the pathology of collagen induced arthritis (CIA) mice. Transcriptome and proteomic sequencing, as well as experimental validation, confirmed that the target of LPS may be the Wnt7b. Knocking down the Wnt7b in CIA mice could effectively alleviate the LPS induced pathology. Furthermore, in the M₀ macrophage-FLS co-culture system, overexpression of Wnt7b in M₀ macrophages promoted the expression of RA pathological factors in FLSs and activated the WNT/CTNNB1 signaling pathway of FLSs. However, knocking down the Wnt7b in M₁ macrophages resulted in the opposite effects. Interestingly, in the M₀ macrophage-FLS co-culture system, overexpression of Wnt7b in M₀ macrophages could enhance the expression of frizzled class receptor 8 (FZD8) on FLSs, activating the Wnt/β-catenin signaling pathway of FLSs. However, knocking down the FZD8 in FLSs after overexpression of Wnt7b could interfere with the effects of overexpression of Wnt7b. In addition, adding LPS to M₀ macrophages promoted the FZD8 expression of co-cultured FLSs and activated the Wnt/β-catenin signaling pathway. Knocking down FZD8 in FLSs after adding LPS to M0 macrophages could interfere with the effects of LPS.</p><p><strong>Conclusion: </strong>This study suggested that circulating LPS stimulated macrophages to secrete Wnt7b, which acted as a messenger molecule and bound to the FZD8 receptor on the FLSs cell membrane in the synovial microenvironment, promoting the activation of the Wnt/β-catenin signaling pathway in FLSs and leading to RA.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unanswered questions on palmitic acid-driven neuroimmune inflammation in atopic dermatitis: a commentary on Chen et al.","authors":"Bo Jiang, Hongjun Liu","doi":"10.1007/s00011-026-02319-1","DOIUrl":"10.1007/s00011-026-02319-1","url":null,"abstract":"<p><p>This commentary provides a critical appraisal of the recent study by Chen and colleagues, which demonstrated that cutaneous palmitic acid (PA) aggravates atopic dermatitis (AD) by driving S-palmitoylation of transient receptor potential vanilloid 1 (TRPV1) in sensory neurons and Mas-related G protein-coupled receptor B2 (MRGPRB2) in mast cells, with the serum/glucocorticoid regulated kinase 1 (SGK1)/neural precursor cell expressed developmentally downregulated protein 4-like (NEDD4L) axis serving as a critical contextual regulator. While the original study offers compelling in vivo genetic validation, several mechanistic and translational questions remain unresolved. Here, we prioritize three areas for future investigation: first, the upstream sources of elevated cutaneous PA-whether derived from keratinocyte lipogenesis, systemic circulation, or microbial production-remain undefined and warrant cell-type-specific genetic interrogation complemented by stable-isotope tracing, spatial lipidomics, and germ-free models. Second, the functional divergence of S-palmitoylation on TRPV1 (promoting degradation) versus MRGPRB2 (conferring stabilization) suggests involvement of distinct palmitoyl acyltransferases (PATs) or context-dependent effects; we propose testable hypotheses including the candidate PAT zDHHC4 for TRPV1 and advocate for cell-based reconstitution, cysteine-mutant rescue, and PAT screening approaches. Third, the anatomical divergence in spinal inflammation between nape and ear models raises questions about the generalizability of central neuroimmune engagement across AD phenotypes, with implications for preclinical model selection and clinical subset stratification. Addressing these questions will clarify whether the PA-palmitoylation-neuroimmune axis represents a tractable therapeutic target and will inform the development of precision interventions that interrupt this pathway without disrupting broader homeostatic palmitoylation, while recognizing that current lack of cell-type-specific palmitoylation inhibitors remains a major hurdle.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathway-level proteomics identifies subcellular trafficking dysregulation as a molecular signature in severe traumatic brain injury.","authors":"Logan R Van Nynatten, David Tweddell, Mark Daley, Gediminas Cepinskas, John Basmaji, Marat Slessarev, Douglas D Fraser","doi":"10.1007/s00011-026-02287-6","DOIUrl":"10.1007/s00011-026-02287-6","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) remains a leading cause of death and disability worldwide in intensive care units, yet no targeted neuroprotective therapies exist despite over 300 clinical trials. This therapeutic failure stems partly from biological heterogeneity and the limitations of single-biomarker approaches that cannot capture the multifaceted pathophysiology of secondary brain injury. Systems biology approaches examining dysregulated pathways rather than isolated proteins may reveal candidate endotypes suitable for patient stratification and identify potential therapeutic targets.</p><p><strong>Methods: </strong>We conducted an exploratory, case-control study, in adult critically-ill patients comparing 10 severe TBI (sTBI) patients (median GCS 5.5) with 10 age-and sex-matched healthy controls. Plasma samples were collected upon admission to the ICU, within 24 h of injury. High-throughput proximity extension assays quantified 1196 plasma proteins, identifying multiple differentially expressed proteins. Gene set enrichment analysis interrogated Reactome pathways and Gene Ontology terms. Protein-protein interaction networks were constructed using the STRING database, and associations between enriched pathways and clinical variables were examined.</p><p><strong>Results: </strong>We identified 348 significantly differentially abundant proteins between groups. Gene set enrichment analysis revealed 19 enriched Reactome pathways and 12 Gene Ontology terms, predominantly reflecting immune activation, inflammation, cellular stress responses, and intracellular trafficking. Strikingly, membrane trafficking pathways, including clathrin-mediated endocytosis and Golgi transport, emerged as significantly enriched, representing an underrecognized mechanism in sTBI pathophysiology. Protein-protein interaction analysis identified four functional clusters, with IL6 and IL10 as densely connected hub proteins coordinating inflammatory responses. Membrane trafficking pathways were associated with clinical outcomes including both length of hospital and intensive care unit stay, as well as need for neurosurgical intervention, in sTBI patients.</p><p><strong>Conclusions: </strong>By profiling the expression of 1196 plasma proteins in parallel, this study provides one of the most comprehensive proteomic characterizations of critically-ill adults with severe traumatic brain injury to date. Systems biology analyses suggest that sTBI may trigger coordinated pathway-level dysregulation extending beyond inflammation to include subcellular trafficking machinery. The association between membrane trafficking pathways and clinical outcomes suggests these may represent a candidate molecular endotype with prognostic relevance. These hypothesis-generating findings support pathway-based approaches for patient stratification and therapeutic targeting in sTBI, though validation in larger cohorts is required.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}