Journal of Neuroinflammation最新文献

{"title":"Central microglia-adenosine-related signaling impairs bone-tendon interface repair via sympathetic ADRB2 activation.","authors":"Tingmo Huang, Liyang Wan, Ruixue Du, Liyue Zeng, Wenjie Li, Feifei Yuan, Hongbin Lu","doi":"10.1186/s12974-026-03977-y","DOIUrl":"10.1186/s12974-026-03977-y","url":null,"abstract":"<p><p>Bone-tendon interface (BTI) injuries pose a major clinical challenge because surgical repair often fails to restore the native enthesis and its structural and mechanical integrity. Although local repair mechanisms have been extensively studied, whether central neuroimmune circuits contribute to BTI healing remains unclear. Here, using a murine rotator cuff injury model, we provide evidence that BTI injury engages a sensory-central-sympathetic regulatory axis that contributes to impaired repair. BTI injury activated sensory afferent signaling and was associated with microglia-mediated neuroinflammation in the hypothalamic paraventricular nucleus (PVN), reduced PVN neuronal activity, and increased central adenosine-related signaling. Chemogenetic activation of PVN microglia suppressed PVN neuronal activity, enhanced sympathetic-associated changes, and impaired BTI healing, whereas microglial inhibition produced the opposite effects. Metabolomic, microdialysis, and pharmacological analyses identified extracellular adenosine as a microglia-associated signaling mediator, likely involving A1R-expressing PVN neurons. Downstream, increased sympathetic signaling at the healing interface was associated with elevated β2-adrenergic receptor (ADRB2) activity and reduced osteogenic and chondrogenic factor expression. Local ADRB2 blockade improved molecular, structural, and histological indices of BTI repair, supporting ADRB2 as a peripheral effector node of this neuroimmune-sympathetic pathway. Together, these findings suggest that central microglia-adenosine-related signaling contributes to BTI repair impairment through sympathetic ADRB2 activation. Targeting central neuroimmune signaling or local ADRB2 activity may provide potential strategies for improving BTI healing.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subcutaneous transplantation of lung organoids ameliorates vascular dementia via the IGFBP7-Ago2 mediated lung-brain axis.","authors":"Qihang Luo, Jiajia Yang, Jiabao Huang, Nanhe Lin, Wenqing Liu, Ziyan Huang, Hongjiang Wang, Jiahui Yao, Jiayi Xiao, Haiyue Zhu, Xianshen Sha, Guangyao Liang, Yun Xie, Zhenwen Liang, Qiuhua Yu, Chuhuai Wang, Shengwei Jiang","doi":"10.1186/s12974-026-03957-2","DOIUrl":"10.1186/s12974-026-03957-2","url":null,"abstract":"<p><p>Vascular dementia (VaD), whose leading cause is chronic cerebral hypoperfusion (CCH), currently has no approved effective disease-modifying therapies. The lung-brain axis mediates crosstalk between the lung and the nervous system, yet the specific mediators underlying its role in VaD remain unclear. This study demonstrated that subcutaneous transplantation of lung organoids (LO) ameliorated cognitive dysfunction in a mouse model of bilateral common carotid artery stenosis (BCAS). We showed that BCAS-induced CCH downregulated pulmonary expression of insulin-like growth factor-binding protein 7 (IGFBP7), a key mediator of the lung-brain axis. LO transplantation restored​circulating IGFBP7, which translocated to the brain and acted directly on microglia by binding to Argonaute2 (Ago2), thereby inhibiting pro-inflammatory signaling pathways, reducing neurovascular damage and neuroinflammation, and alleviating​peripheral lung injury caused by CCH. Notably, LO transplantation concurrently restores cerebral function and pulmonary homeostasis, with concurrent recovery of endogenous pulmonary IGFBP7 expression in BCAS mice, indicating concurrent improvement of both brain and lung pathology through lung-brain axis crosstalk. This study confirmed that LO transplantation represented an effective biotherapy for VaD and identified the IGFBP7-Ago2 axis as a core regulatory pathway of the lung-brain axis. These findings provide mechanistic insights into the pathogenesis of VaD and highlight that IGFBP7 is a potential therapeutic target for restoring inter-organ crosstalk in dementia.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iPLA2β-dependent phospholipid remodeling drives ZIKV-induced neuroinflammation and neurological injury.","authors":"Li Jiao, Wenxin Shao, Ying Xie, Sirong Li, Jiahong Gao, Jianyu Xu, Rui Tong, Dehong Li, Qiangming Sun","doi":"10.1186/s12974-026-03973-2","DOIUrl":"10.1186/s12974-026-03973-2","url":null,"abstract":"<p><p>Zika virus (ZIKV) infection of the developing brain induces neuroinflammatory responses that can restrict viral replication but may also contribute to neurological injury when dysregulated. Although neuronal phospholipid homeostasis is critical for membrane integrity and synaptic function, how ZIKV infection reprograms lipid metabolism to drive neuropathogenesis remains unclear. Here, we identify calcium-independent phospholipase A2β (iPLA2β) as a key mediator of ZIKV-induced neuronal lipid remodeling. iPLA2β is rapidly upregulated in neurons and in the neonatal brain following infection, and its expression is promoted by the viral envelope protein, which interacts with iPLA2β in neurons. Genetic ablation of iPLA2β reduces viral burden in the developing brain and in primary neurons and disrupts ZIKV-induced phospholipid remodeling, characterized by altered arachidonic acid-containing phospholipids and depletion of docosahexaenoic acid-enriched species. Importantly, sustained iPLA2β activity promotes phospholipid remodeling that supports efficient ZIKV replication, thereby increasing viral burden and contributing to a pro-inflammatory lipid environment. This is associated with increased prostaglandin E₂ production, glial activation, and neuronal loss. Both genetic and pharmacological inhibition of iPLA2β partially restores phospholipid homeostasis and reduces viral burden, accompanied by attenuation of neuroinflammatory responses. Functionally, targeting iPLA2β improves survival and neurobehavioral outcomes and mitigates long-term cognitive deficits following neonatal ZIKV infection. Collectively, these findings support iPLA2β-dependent phospholipid remodeling as a host process that facilitates ZIKV replication and links infection to neuroinflammation and neurological injury, highlighting iPLA2β as a potential therapeutic target in ZIKV-associated neuropathogenesis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An interpretable clinical-proteomic framework identifies baseline neuroinflammatory proteomic patterns associated with post-thrombectomy mortality.","authors":"Min Xiao, Niu Qiao, Ruihong Zhang, Rong Xi, Xiaojun Ma, Huanyin Li, Hai-Qian Zhou, Yang Liu, Jixian Lin","doi":"10.1186/s12974-026-03971-4","DOIUrl":"10.1186/s12974-026-03971-4","url":null,"abstract":"<p><p>Endovascular thrombectomy (EVT) is the standard reperfusion therapy for emergent large-vessel occlusion; however, nearly 20% of EVT-treated patients still die within one year. Although early clinical indicators can help stratify post-EVT prognosis, the baseline neuroinflammatory biology associated with fatal outcomes after EVT remains incompletely characterized. In this prospective study of 148 EVT-treated patients, including 30 patients who died within 1 year, we profiled pre-procedure serum proteins using the Olink 384 Inflammation panel and applied an exploratory clinical-proteomic framework. A clinical-only model was used to define higher-risk and lower-risk clinical strata. We then mapped these strata to baseline proteomic patterns through differential expression and annotation-supported candidate mapping. Higher-risk phenotypes were associated with a candidate inflammation- and immune-receptor-related baseline protein pattern. Lower-risk phenotypes were associated with a candidate adhesion/extracellular-matrix-related baseline protein pattern. These internally derived findings suggest that poor outcomes after EVT are associated with candidate baseline inflammatory and tissue-structure-related proteomic patterns. This study provides a neuroinflammation-focused framework for hypothesis generation and candidate prioritization, but the findings require external validation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the lung-brain axis in influenza: from pulmonary infection to central nervous system injury.","authors":"Xindan Liang, Xiaoqi Wang, Zhibin Wang, Chunjing Chen, Ling Li, Fangguo Lu","doi":"10.1186/s12974-026-03958-1","DOIUrl":"10.1186/s12974-026-03958-1","url":null,"abstract":"<p><p>Influenza viruses are respiratory pathogens of the family Orthomyxoviridae. Among the four recognized types, influenza A virus (IAV) is the primary cause of seasonal epidemics and pandemics. Continuous antigenic drift facilitates immune evasion, whereas occasional antigenic shift drives the emergence of novel hemagglutinin (HA) and neuraminidase (NA) subtype combinations. Although influenza is primarily characterized by respiratory manifestations, it can also cause severe central nervous system (CNS) complications, including encephalitis, collectively referred to as influenza-associated encephalopathy (IAE), which is associated with poor clinical outcomes and remains frequently overlooked. The neurotropic potential of influenza viruses remains controversial. Although vaccination and antiviral therapies effectively reduce influenza-related morbidity and mortality, specific preventive and therapeutic strategies for influenza-associated CNS complications remain limited. This review synthesizes current evidence on the neuroinvasive characteristics of influenza viruses, including susceptibility factors, viral determinants, host responses, pathogenic mechanisms, therapeutic strategies, and prognostic indicators. Particular emphasis is placed on the mechanisms underlying CNS injury, including both direct viral invasion and indirect injury mediated by dysregulated immune and inflammatory responses. By integrating these emerging mechanistic insights, this review proposes a lung-brain axis framework to explain the bidirectional communication between pulmonary infection and neurological injury during influenza. This framework provides an updated perspective on the pathogenesis of IAE, identifies potential therapeutic targets, and may facilitate future studies aimed at improving early diagnosis, risk stratification, and the development of mechanism-based interventions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR1 signaling as a common injury pathway in retinal degeneration.","authors":"Sarah Elbaz-Hayoun, Lian Omari, Shlomit Jaskoll, Adi Kramer, Batya Rinsky, Maya Eiger-Moscovich, Ying Song, Joshua L Dunaief, Sandro De Zanet, Stefanos Apostolopoulos, Carlos Ciller, Itay Chowers","doi":"10.1186/s12974-026-03952-7","DOIUrl":"10.1186/s12974-026-03952-7","url":null,"abstract":"<p><p>Inflammation is a key driver of atrophic Age-Related Macular Degeneration (aAMD), and also plays a role in Inherited Retinal Degenerations (IRDs), two major causes of irreversible visual loss. We previously demonstrated that the C-C chemokine receptor type 1 (CCR1) is upregulated in monocytes from AMD patients, and that it mediates the recruitment of neurotoxic macrophages and activates Müller glial cells in rodent model of photic retinal injury. Here we report that CCR1 is expressed in Müller glia in eyes affected by AMD and that variants in CCR1 are potentially associated with the rate of macular atrophy progression in AMD. We also show that Ccr1 deletion is associated with reduced inflammation, and with rescue of photoreceptor integrity and function in Crb1^rd8/rd8 mice and in Pde6b^rd10 mice, two models of genetically-driven retinal degeneration. Finally, we demonstrate that treatment with small molecule CCR1 antagonists delayed photoreceptor loss in Pde6b^rd10 mice. These data suggest that CCR1 is a mediator of retinal inflammation and injury in different forms of retinal degeneration, and that CCR1 may serve as a novel therapeutic target for atrophic AMD and IRDs.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A BRD4/p300/SP1 epigenetic cascade drives microglial P2X4R transcription and promotes neuropathic pain.","authors":"Daojuan Wang, Tingyu Wang, Yin Li, Xinye Yu, Shenquan Cai, Chun Wang, Yihan Wang, Zhengquan Zhu, Ying Huang, Yong Wang, Wangsen Cao, Gaojian Tao","doi":"10.1186/s12974-026-03965-2","DOIUrl":"10.1186/s12974-026-03965-2","url":null,"abstract":"<p><p>Persistent upregulation of the purinergic receptor P2X4R is strongly associated with microglial activation in neuropathic pain, yet the epigenetic mechanisms linking chromatin remodeling to its dysregulation remain unclear. Here, we delineate a hierarchical epigenetic cascade that promotes transcriptional activation of P2X4R in spinal microglia following nerve injury. In a mouse spared nerve injury (SNI) model, microglial activation was accompanied by increased expression of P2X4R and the histone acetyltransferase p300, together with enhanced histone acetylation (H3K9ac, H3K27ac, H4K5ac, and H4K8ac) and increased chromatin accessibility at the P2rx4 promoter. Microglia-specific deletion of p300 blunted injury-induced histone acetylation and suppressed P2X4R upregulation. We further demonstrate that the acetylation reader BRD4 is recruited to these regions and cooperates with the transcription factor SP1 to drive P2rx4 transcription, supported by chromatin analyses revealing inducible assembly of a BRD4-p300-SP1 axis. Disruption of this cascade via p300 inhibition (C646) or BRD4 blockade (JQ1) attenuated spinal neuroinflammation and alleviated nociceptive hypersensitivity. Notably, reactivation of P2X4R by BzATP largely reversed the analgesic effects of BRD4 inhibition, establishing P2X4R as a critical downstream effector. Collectively, these findings support a p300-BRD4-SP1 epigenetic cascade linking chromatin remodeling to microglia-mediated neuropathic pain, highlighting this pathway as a potential therapeutic target.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming via SIRT2-deficient microglial large extracellular vesicles ameliorates alzheimer's pathology.","authors":"Xiaolu Tang, Rui Chen, Jiawei Xing, Qing Huang, Lv Luo, Chaoyue Ouyang, Fubin Ma, Jie Wen, Jiahao Zhang, Lingyun Kong, Yujie Cai, Yan Wang, Lili Cui","doi":"10.1186/s12974-026-03956-3","DOIUrl":"10.1186/s12974-026-03956-3","url":null,"abstract":"<p><strong>Background: </strong>Current therapies for Alzheimer's disease (AD) offer only symptomatic relief, highlighting the urgent need for disease-modifying approaches capable of halting or reversing neurodegeneration. Extracellular vesicles (EVs) have attracted growing interest as therapeutic vehicles owing to their inherent capacity to bypass the blood-brain barrier and deliver complex biological cargo to the central nervous system.</p><p><strong>Methods: </strong>Here, we examined whether large EVs (LEVs) derived from microglia with stable Sirtuin-2 knockdown (SIRT2-KD) confer the neuroprotective effects associated with SIRT2 inhibition. LEVs harvested from SIRT2-KD microglia were administered intranasally to APP/PS1 mice. We assessed microglial uptake of LEVs, along with subsequent changes in cellular metabolism, migration toward amyloid-beta (Aβ) plaques, phagocytic activity, and downstream pathological and behavioral outcomes. Proteomic and acetylomic profiling were employed to characterize the molecular cargo of LEVs-SIRT2-KD.</p><p><strong>Results: </strong>LEVs-SIRT2-KD were readily internalized by microglia in vivo following intranasal delivery. Uptake of these vesicles markedly enhanced microglial bioenergetics, driving coordinated upregulation of both oxidative phosphorylation and glycolysis. This metabolic shift was accompanied by improved microglial recruitment to Aβ plaques and increased phagocytic clearance. Consequently, treated mice showed reduced Aβ plaque deposition, restored synaptic integrity, and reversal of cognitive deficits. Proteomic and acetylomic analyses revealed that LEVs-SIRT2-KD are selectively enriched in proteins and acetylation modifications linked to energy metabolism and phagocytic function, offering a mechanistic basis for the observed metabolic reprogramming.</p><p><strong>Conclusion: </strong>Together, these results identify LEVs as a critical vesicle subtype mediating the effects of SIRT2 knockdown and support a cell-free therapeutic strategy for AD centered on EVs-driven metabolic reprogramming of microglia.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bidirectional crosstalk between TRP channels and Toll-like receptors in inflammation and host defense.","authors":"Qianrui Zeng, Chi Zhang, Na Xie, Shutong Chen, Chang Liu, Haodang Luo, Xiaoxing You","doi":"10.1186/s12974-026-03966-1","DOIUrl":"10.1186/s12974-026-03966-1","url":null,"abstract":"<p><p>Integrating physicochemical environmental cues with pathogen detection is essential for an effective and balanced host defense. While Toll-like receptors (TLRs) detect pathogen-associated molecular patterns (PAMPs), transient receptor potential (TRP) ion channels detect specific physicochemical shifts characteristic of inflamed tissues, including extracellular acidosis, hyperosmolarity, oxidative stress, and mechanical perturbations of the lipid bilayer. Emerging evidence indicates that these two sensory systems interact via a bidirectional signaling axis. This review summarizes recent advances in the molecular mechanisms of TRP-TLR crosstalk, focusing on the three principal modes: direct physical coupling, indirect functional coupling via second messengers, and spatial co-organization within membrane microdomains. We examine how TLR signaling regulates TRP channel expression and post-translational modification. Reciprocally, we detail how TRP-mediated ionic fluxes modulate TLR ligand recognition, signal amplification, and effector functions, including phagocytosis and cytokine secretion. Crucially, we illustrate how the dysregulation of this subcellular crosstalk scales up to drive tissue pathologies, including neuropathic pain sensitization, central neuroinflammation, and barrier organ dysfunction. The TRP-TLR axis represents a convergence of immune and sensory signaling. Understanding this interaction provides a basis for identifying novel therapeutic targets for infectious and inflammatory diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FPR2 deficiency alleviates LPS-induced depressive-like behaviors in mice by suppressing the microglial CSF1/NLRP3 inflammasome pathway.","authors":"Hanqi Wang, Yijun Chen, Junna Chang, Zhen Liu, Yang Yu","doi":"10.1186/s12974-026-03963-4","DOIUrl":"10.1186/s12974-026-03963-4","url":null,"abstract":"<p><p>Depression is one of the most prevalent psychiatric disorders worldwide, yet its pathogenesis remains unclear. Here, we aimed to investigate the effects of formyl peptide receptor 2 (FPR2), a key regulator of innate immunity and inflammation, on lipopolysaccharide (LPS)-induced depression-related behaviors in mice after intraperitoneal administration, and to elucidate its regulatory mechanisms in microglia. FPR2 knockout (Fpr2^-/-) significantly attenuated LPS-induced depressive and anxiety-like behaviors in mice. LPS markedly increased FPR2 expression in microglia of the prefrontal cortex (PFC) and hippocampus, while only a minimal increase was observed in neurons. FPR2 deficiency alleviated LPS-induced microglial activation and reduced neuronal synaptic alterations. RNA sequencing and validation experiments confirmed that FPR2 deletion substantially decreased LPS-induced microglial NLRP3 inflammasome activation and IL-1β levels in the brain. Mechanistically, FPR2 regulated downstream NLRP3 activation by modulating CSF1, and FPR2/CSF1 activation was governed by its upstream ligand, serum amyloid A (SAA). Analysis of public clinical datasets revealed that SAA1 levels were significantly upregulated in the orbital ventral PFC of patients with major depressive disorder (MDD) and in the plasma of patients with late-life depression. These findings demonstrate that the SAA/FPR2/CSF1/NLRP3 pathway mediates LPS-induced depressive-like behaviors by regulating microglial activation and neuroinflammation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}