Brain, Behavior, and Immunity最新文献

{"title":"Metagenomic symphony of the intestinal ecosystem: How the composition affects the mind","authors":"Stefanie Malan-Müller ,&nbsp;David Martín-Hernández ,&nbsp;Javier R. Caso ,&nbsp;Jelle Matthijnssens ,&nbsp;Amanda Rodríguez-Urrutia ,&nbsp;Christopher A. Lowry ,&nbsp;Juan C. Leza","doi":"10.1016/j.bbi.2024.09.033","DOIUrl":"10.1016/j.bbi.2024.09.033","url":null,"abstract":"<div><div>Mental health disorders and neurodegenerative diseases place a heavy burden on patients and societies, and, although great strides have been made to understand the pathophysiology of these conditions, advancement in drug development is lagging. The importance of gastrointestinal health in maintaining overall health and preventing disease is not a new concept. Hundreds of years ago, healers from various cultures and civilizations recognized the crucial role of the gut in sustaining health. More than a century ago, scientists began exploring the restorative effects of probiotics, marking the early recognition of the importance of gut microbes. The omics era brought more enlightenment and enabled researchers to identify the complexity of the microbial ecosystems we harbour, encompassing bacteria, eukaryotes (including fungi), archaea, viruses, and other microorganisms. The extensive genetic capacity of the microbiota is dynamic and influenced by the environment. The microbiota therefore serves as a significant entity within us, with evolutionarily preserved functions in host metabolism, immunity, development, and behavior. The significant role of the bacterial gut microbiome in mental health and neurodegenerative disorders has been realized and described within the framework of the microbiota-gut-brain axis. However, the bacterial members do not function unaccompanied, but rather in concert, and there is a substantial knowledge gap regarding the involvement of non-bacterial microbiome members in these disorders. In this review, we will explore the current literature that implicates a role for the entire metagenomic ensemble, and how their complex interkingdom relationships could influence CNS functioning in mental health disorders and neurodegenerative diseases.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathways to maternal health inequities: Structural racism, sleep, and physiological stress","authors":"Lisa M. Christian ,&nbsp;Ryan L. Brown ,&nbsp;Judith E. Carroll ,&nbsp;Julian F. Thayer ,&nbsp;Tené T. Lewis ,&nbsp;Shannon L. Gillespie ,&nbsp;Christopher P. Fagundes","doi":"10.1016/j.bbi.2024.09.037","DOIUrl":"10.1016/j.bbi.2024.09.037","url":null,"abstract":"<div><div>Racial inequities in health are vast and well-documented, particularly regarding maternal and infant health. Sleep health, including but not limited to duration and quality, is central to overall health and well-being. However, research has not adequately addressed how racism embedded in structures and systems, in addition to individual experiences, may affect maternal health by impacting sleep. In this critical review, we aim to 1) synthesize findings, emphasizing collaborative studies within our group, 2) highlight gaps in knowledge, and 3) propose a theoretical framework and methodological approach for moving the field forward. Specifically, we focus on findings and future directions linking perinatal sleep, cardiovascular and immune function, and racial disparities in maternal health. Because too few studies look beyond individual-level determinants of sleep deficiencies among Black Americans, we assert a critical need for research that bridges multiple levels of analysis (e.g., individual, community, society) and provides recommendations for specific health parameters that researchers in this area can target. Although the need to understand and address perinatal health disparities is clear, the goal of identifying multilevel mechanisms underlying how racism in one’s environment and daily life may interact to affect health extends far beyond pregnancy research.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371007","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}

{"title":"Communication of inflammation","authors":"Michael B. Hennessy","doi":"10.1016/j.bbi.2024.09.036","DOIUrl":"10.1016/j.bbi.2024.09.036","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 397-398"},"PeriodicalIF":8.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364417","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}

{"title":"Microglial TREM2 promotes phagocytic clearance of damaged neurons after status epilepticus","authors":"Dale B. Bosco ,&nbsp;Vaclav Kremen ,&nbsp;Koichiro Haruwaka ,&nbsp;Shunyi Zhao ,&nbsp;Lingxiao Wang ,&nbsp;Blake A. Ebner ,&nbsp;Jiaying Zheng ,&nbsp;Manling Xie ,&nbsp;Aastha Dheer ,&nbsp;Jadyn F. Perry ,&nbsp;Abhijeet Barath ,&nbsp;Aivi T. Nguyen ,&nbsp;Gregory A. Worrell ,&nbsp;Long-Jun Wu","doi":"10.1016/j.bbi.2024.09.034","DOIUrl":"10.1016/j.bbi.2024.09.034","url":null,"abstract":"<div><div>In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. Microglial TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer’s disease and amyotrophic lateral sclerosis. However, little is known about how TREM2 affects microglial function within epileptogenesis. To investigate this, we utilized male TREM2 knockout (KO) mice within the intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both the severity of acute <em>status epilepticus</em> and the number of spontaneous recurrent seizures characteristic of chronic focal epilepsy. Phagocytic clearance of damaged neurons by microglia was also impaired by TREM2 KO and reduced phagocytic activity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between expression of the microglial phagocytic marker CD68 and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity are important to epileptogenic pathology.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 540-555"},"PeriodicalIF":8.8,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364418","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}

{"title":"Upregulation of delta opioid receptor by meningeal interleukin-10 prevents relapsing pain","authors":"Kufreobong E. Inyang ,&nbsp;Jaewon Sim ,&nbsp;Kimberly B. Clark ,&nbsp;Matan Geron ,&nbsp;Karli Monahan ,&nbsp;Christine Evans ,&nbsp;Patrick O’Connell ,&nbsp;Sophie Laumet ,&nbsp;Bo Peng ,&nbsp;Jiacheng Ma ,&nbsp;Cobi J. Heijnen ,&nbsp;Robert Dantzer ,&nbsp;Grégory Scherrer ,&nbsp;Annemieke Kavelaars ,&nbsp;Matthew Bernard ,&nbsp;Yasser A. Aldhamen ,&nbsp;Joseph K. Folger ,&nbsp;Alexis Bavencoffe ,&nbsp;Geoffroy Laumet","doi":"10.1016/j.bbi.2024.09.031","DOIUrl":"10.1016/j.bbi.2024.09.031","url":null,"abstract":"<div><div>Chronic pain often includes periods of transient amelioration and even remission that alternate with severe relapsing pain. While most research on chronic pain has focused on pain development and maintenance, there is a critical unmet need to better understand the mechanisms that underlie pain remission and relapse. We found that interleukin (IL)-10, a pain resolving cytokine, is produced by resident macrophages in the spinal meninges during remission from pain and signaled to IL-10 receptor-expressing sensory neurons. Using unbiased RNA-sequencing, we identified that IL-10 upregulated expression and antinociceptive activity of δ-opioid receptor (δOR) in the dorsal root ganglion. Genetic or pharmacological inhibition of either IL-10 signaling or δOR triggered relapsing pain. Overall, our findings, from electrophysiology, genetic manipulation, flow cytometry, pharmacology, and behavioral approaches, indicate that remission of pain is not simply a return to the naïve state. Instead, remission is an adapted homeostatic state associated with lasting pain vulnerability resulting from persisting neuroimmune interactions within the nociceptive system. Broadly, this sheds light on the elusive mechanisms underlying recurrence a common aspect across various chronic pain conditions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 399-410"},"PeriodicalIF":8.8,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341897","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}

{"title":"Inflammatory pain resolution by mouse serum-derived small extracellular vesicles","authors":"Zhucheng Lin ,&nbsp;Xuan Luo ,&nbsp;Jason R. Wickman ,&nbsp;Deepa Reddy ,&nbsp;Jason T. DaCunza ,&nbsp;Richa Pande ,&nbsp;Yuzhen Tian ,&nbsp;Ezgi E. Kasimoglu ,&nbsp;Vivian Triana ,&nbsp;Jingyun Lee ,&nbsp;Cristina M. Furdui ,&nbsp;Desmond Pink ,&nbsp;Ahmet Sacan ,&nbsp;Seena K. Ajit","doi":"10.1016/j.bbi.2024.09.032","DOIUrl":"10.1016/j.bbi.2024.09.032","url":null,"abstract":"<div><div>Current treatments for chronic pain have limited efficacy and significant side effects, warranting research on alternative strategies for pain management. One approach involves using small extracellular vesicles (sEVs), or exosomes, to transport beneficial biomolecular cargo to aid pain resolution. Exosomes are 30–150 nm sEVs that can be beneficial or harmful depending on their source and cargo composition. We report a comprehensive multi-modal analysis of different aspects of sEV characterization, miRNAs, and protein markers across sEV sources. To investigate the short- and long-term effects of mouse serum-derived sEVs in pain modulation, sEVs from naïve control or spared nerve injury (SNI) model male donor mice were injected intrathecally into naïve male recipient mice. These sEVs transiently increased basal mechanical thresholds, an effect mediated by opioid signaling as this outcome was blocked by naltrexone. Mass spectrometry of sEVs detected endogenous opioid peptide leu-enkephalin. sEVs from naïve female mice have higher levels of leu-enkephalin compared to male, matching the analgesic onset of leu-enkephalin in male recipient mice. In investigating the long-term effect of sEVs, we observed that a single prophylactic intrathecal injection of sEVs two weeks prior to induction of the pain model in recipient mice accelerated recovery from inflammatory pain after complete Freund’s adjuvant (CFA) injection. Our exploratory studies examining immune cell populations in spinal cord and dorsal root ganglion using ChipCytometry suggested alterations in immune cell populations 14 days post-CFA. Flow cytometry confirmed increases in CD206⁺ macrophages in the spinal cord in sEV-treated mice. Collectively, these studies demonstrate multiple mechanisms by which sEVs can attenuate pain.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 422-441"},"PeriodicalIF":8.8,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep loss-induced oncogenic pathways are mediated via the neuron-specific interleukin-1 receptor accessory protein (AcPb)","authors":"Yool Lee ,&nbsp;Erika L. English ,&nbsp;Catherine M. Schwartzmann ,&nbsp;Yiyong Liu ,&nbsp;James M. Krueger","doi":"10.1016/j.bbi.2024.09.029","DOIUrl":"10.1016/j.bbi.2024.09.029","url":null,"abstract":"<div><div>Interleukin-1β (IL1), a pleiotropic cytokine, is involved in sleep regulation, tumor ontogeny, and immune responses. IL1 receptor adaptor proteins, including the IL1 receptor accessory protein (AcP), and its neuron-specific isoform, AcPb, are required for IL1 signaling. The AcPb isoform is resultant from alternate splicing of the AcP transcript. Our previous studies using AcPb null (AcPb^-/-) mice characterized its participation in sleep regulation and emergent neuronal/glial network properties. Here, we investigated the impact of acute sleep disruption (SD) on brain cancer-related pathways in wild-type (WT) and AcPb^-/- mice, employing RNA sequencing methods. In WT mice, SD increased AcPb mRNA levels, but not AcP mRNA, confirming prior similar work in rats. Transcriptome and pathway enrichment analyses demonstrated significant alterations in cancer, immune, and viral disease-related pathways in WT mice after SD, which were attenuated in AcPb^-/- mice including multiple upregulated Src phosphorylation-signaling-dependent genes associated with cancer progression and metastasis. Our RNAseq findings, were analyzed within the context of The Cancer Genome Atlas Program (TCGA) data base; revealing an upregulation of sleep- and cancer-linked genes (e.g., IL-17B, IL-17RA, LCN2) across various tumors, including brain tumors, compared to normal tissues. Sleep-linked factors, identified through TCGA analyses, significantly impact patient prognosis and survival, particularly in low-grade glioma (LGG) and glioblastoma multiforme (GBM) patients. Overall, our findings suggest that SD promotes a pro-tumor environment through AcPb-modulated pathways.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 411-421"},"PeriodicalIF":8.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathophysiology, blood biomarkers, and functional deficits after intimate partner violence-related brain injury: Insights from emergency department patients and a new rat model","authors":"Mujun Sun ,&nbsp;Georgia F. Symons ,&nbsp;Gershon Spitz ,&nbsp;William T. O’Brien ,&nbsp;Tamara L Baker ,&nbsp;Jianjia Fan ,&nbsp;Beatriz D. Martins ,&nbsp;Josh Allen ,&nbsp;Lauren P. Giesler ,&nbsp;Richelle Mychasiuk ,&nbsp;Paul van Donkelaar ,&nbsp;Justin Brand ,&nbsp;Brian Christie ,&nbsp;Terence J. O’Brien ,&nbsp;Michael J. O’Sullivan ,&nbsp;Biswadev Mitra ,&nbsp;Cheryl Wellington ,&nbsp;Stuart J. McDonald ,&nbsp;Sandy R. Shultz","doi":"10.1016/j.bbi.2024.09.030","DOIUrl":"10.1016/j.bbi.2024.09.030","url":null,"abstract":"<div><div>Intimate partner violence is a serious, but underappreciated, issue that predominantly affects women and often results in concussion (i.e., mild traumatic brain injury). However, concussion in intimate partner violence is unique because it often involves a concomitant strangulation which may exacerbate or alter the physiology and clinical presentation of the brain injury. Therefore, here we conducted human and rodent studies to provide insight into knowledge gaps related to the detection, pathophysiology, and functional consequences of intimate partner violence-related brain injury. We conducted the first study to analyze blood biomarkers and symptoms of brain injury in intimate partner violence patients presenting to an emergency department within 72 h of concussion. Intimate partner violence concussion patients, some of whom had also experienced a concomitant strangulation, had elevated serum neurofilament light and worse brain injury symptoms compared to healthy control, orthopedic trauma, and non-intimate partner violence concussion groups. We also developed the first rat model of non-fatal strangulation and examined the consequences of strangulation and concussion in isolation and in combination on pathophysiology, blood biomarkers, and behavior at 2 h and 1wk post-injury. Rats exposed to combined strangulation and concussion had exacerbated motor and cognitive deficits, neuroinflammation, and serum glial fibrillary acidic protein levels compared with either injury in isolation. Taken together, these rodent findings demonstrate that a concomitant strangulation modifies and exacerbates concussion pathophysiology, biomarkers, and functional consequences. Overall, these findings provide novel insights into intimate partner violence-related brain injury and provides a foundation for future translational studies.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 383-396"},"PeriodicalIF":8.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the use of immunomethylomics in the characterization of depressed patients: A proof-of-concept study","authors":"Evelien Van Assche ,&nbsp;Christa Hohoff ,&nbsp;Ecem Su Atil ,&nbsp;Sophia M. Wissing ,&nbsp;Alessandro Serretti ,&nbsp;Chiara Fabbri ,&nbsp;Claudia Pisanu ,&nbsp;Alessio Squassina ,&nbsp;Alessandra Minelli ,&nbsp;European College of Neuropsychopharmacology (ECNP) Pharmacogenomics & Transcriptomics Network ,&nbsp;Bernhard T. Baune","doi":"10.1016/j.bbi.2024.09.026","DOIUrl":"10.1016/j.bbi.2024.09.026","url":null,"abstract":"<div><div>Alterations in DNA methylation and inflammation could represent valid biomarkers for the stratification of patients with major depressive disorder (MDD). This study explored the use of DNA-methylation based immunological cell-type profiles in the context of MDD and symptom severity over time.</div><div>In 119 individuals with MDD, DNA-methylation was assessed on whole blood using the Illumina Infinium MethylationEPIC 850 k BeadChip. Quality control and data processing, as well as cell type estimation was conducted using the RnBeads package. The cell type composition was estimated using epigenome-wide DNA methylation signatures, applying the Houseman method, considering six cell types (neutrophils, natural killer cells (NK), B cells, CD4+ T cells, CD8+ T cells and monocytes). Two cytokines (IL-6 and IL-1β) and hsCRP were quantified in serum. We performed a hierarchical cluster analysis on the six estimated cell-types and tested the differences between these clusters in relation to the two cytokines and hsCRP, depression severity at baseline, and after 6 weeks of treatment (celecoxib/placebo + vortioxetine). We performed a second cluster analysis with cell-types and cytokines combined. ANCOVA was used to test for differences across clusters. We applied the Bonferroni correction.</div><div>After quality control, we included 113 participants. Two clusters were identified, cluster 1 was high in CD4+ cells and NK, cluster 2 was high in CD8+ T-cells and B-cells, with similar fractions of neutrophils and monocytes. The clusters were not associated with either of the two cytokines and hsCRP, or depression severity at baseline, but cluster 1 showed higher depression severity after 6 weeks, corrected for baseline (<em>p</em> = 0.0060). The second cluster analysis found similar results: cluster 1 was low in CD8+ T-cells, B-cells, and IL-1β. Cluster 2 was low in CD4+ cells and natural killer cells. Neutrophils, monocytes, IL-6 and hsCRP were not different between the clusters. Participants in cluster 1 showed higher depression severity at baseline than cluster 2 (<em>p</em> = 0.034), but no difference in depression severity after 6 weeks.</div><div>DNA-methylation based cell-type profiles may be valuable in the immunological characterization and stratification of patients with MDD. Future models should consider the inclusion of more cell-types and cytokines for better a prediction of treatment outcomes.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 597-605"},"PeriodicalIF":8.8,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142341883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides","authors":"Josephine Louise Robb ,&nbsp;Frédérick Boisjoly ,&nbsp;Arturo Israel Machuca-Parra ,&nbsp;Adeline Coursan ,&nbsp;Romane Manceau ,&nbsp;Danie Majeur ,&nbsp;Demetra Rodaros ,&nbsp;Khalil Bouyakdan ,&nbsp;Karine Greffard ,&nbsp;Jean-François Bilodeau ,&nbsp;Anik Forest ,&nbsp;Caroline Daneault ,&nbsp;Matthieu Ruiz ,&nbsp;Cyril Laurent ,&nbsp;Nathalie Arbour ,&nbsp;Sophie Layé ,&nbsp;Xavier Fioramonti ,&nbsp;Charlotte Madore ,&nbsp;Stephanie Fulton ,&nbsp;Thierry Alquier","doi":"10.1016/j.bbi.2024.09.027","DOIUrl":"10.1016/j.bbi.2024.09.027","url":null,"abstract":"<div><div>Lipid droplets (LD) are triglyceride storing organelles that have emerged as an important component of cellular inflammatory responses. LD lipolysis via adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral immune and non-immune cells. ATGL elicits both pro- and anti-inflammatory responses in the periphery in a cell-type dependent manner. The present study determined the impact of ATGL inhibition and microglia-specific ATGL genetic loss-of-function on acute inflammatory and behavioural responses to pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines and phagocytosis in mouse primary microglia cultures. Lipase inhibitors (ORlistat and ATGListatin) and LPS led to LD accumulation in microglia. Pan-lipase inhibition with ORlistat alleviated LPS-induced expression of IL-1β and IL-6. Specific inhibition of ATGL had a similar action on CCL2, IL-1β and IL-6 expression in both neonatal and adult microglia cultures. CCL2 and IL-6 secretion were also reduced by ATGListatin or knockdown of ATGL. ATGListatin increased phagocytosis in neonatal cultures independently from LPS treatment. Second, targeted and untargeted lipid profiling revealed that ATGListatin reduced LPS-induced generation of pro-inflammatory prostanoids and modulated ceramide species in neonatal microglia. Finally, the role of microglial ATGL in neuroinflammation was assessed using a novel microglia-specific and inducible ATGL knockout mouse model. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and IL-1β and microglial density. LPS-induced sickness- and anxiety-like behaviours were also reduced in male mice with loss of ATGL in microglia. Together, our results demonstrate potent anti-inflammatory effects produced by pharmacological or genetic inhibition of ATGL-mediated triglyceride lipolysis and thereby propose that supressing microglial LD lipolysis has beneficial actions in acute neuroinflammatory conditions.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"123 ","pages":"Pages 315-333"},"PeriodicalIF":8.8,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}