NLRP3-mediated trained immunity of microglia is involved in the recurrence-like episode of depressive disorders

Wait 5 sec.

Cui L, Li S, Wang S, Wu X, Liu Y, Yu W, et al. Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther. 2024;9:30.PubMed  PubMed Central  Google Scholar Han A, Yeo H, Park MJ, Kim SH, Choi HJ, Hong CW, et al. IL-4/10 prevents stress vulnerability following imipramine discontinuation. J Neuroinflammation. 2015;12:197.PubMed  PubMed Central  Google Scholar Burcusa SL, Iacono WG. Risk for recurrence in depression. Clin Psychol Rev. 2007;27:959–85.PubMed  PubMed Central  Google Scholar Buckman JEJ, Underwood A, Clarke K, Saunders R, Hollon SD, Fearon P, et al. Risk factors for relapse and recurrence of depression in adults and how they operate: A four-phase systematic review and meta-synthesis. Clin Psychol Rev. 2018;64:13–38.PubMed  PubMed Central  Google Scholar Monroe SM, Anderson SF, Harkness KL. Life stress and major depression: the mysteries of recurrences. Psychol Rev. 2019;126:791–816.PubMed  Google Scholar Harkness KL, Hayden EP, Lopez-Duran NL. Stress sensitivity and stress sensitization in psychopathology: an introduction to the special section. J Abnorm Psychol. 2015;124:1–3.PubMed  Google Scholar Maes M, Jirakran K, Vasupanrajit A, Niu M, Zhou B, Stoyanov DS, et al. The recurrence of illness (ROI) index is a key factor in major depression that indicates increasing immune-linked neurotoxicity and vulnerability to suicidal behaviors. Psychiatry Res. 2024;339:116085.PubMed  Google Scholar Franklin TC, Wohleb ES, Zhang Y, Fogaca M, Hare B, Duman RS. Persistent increase in microglial RAGE contributes to chronic stress-induced priming of depressive-like behavior. Biol Psychiatry. 2018;83:50–60.PubMed  Google Scholar Netea MG, Quintin J, van der Meer JW. Trained immunity: a memory for innate host defense. Cell Host Microbe. 2011;9:355–61.PubMed  Google Scholar Ochando J, Mulder WJM, Madsen JC, Netea MG, Duivenvoorden R. Trained immunity - basic concepts and contributions to immunopathology. Nat Rev Nephrol. 2023;19:23–37.PubMed  Google Scholar Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018;556:332–8.PubMed  PubMed Central  Google Scholar Yuan M, Yang B, Rothschild G, Mann JJ, Sanford LD, Tang X, et al. Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential. Signal Transduct Target Ther. 2023;8:309.PubMed  PubMed Central  Google Scholar Post RM. Epigenetic basis of sensitization to stress, affective episodes, and stimulants: implications for illness progression and prevention. Bipolar Disord. 2016;18:315–24.PubMed  Google Scholar Neher JJ, Cunningham C. Priming microglia for innate immune memory in the brain. Trends Immunol. 2019;40:358–74.PubMed  Google Scholar Feng Y, Lin L, Wu T, Feng Y, Liang F, Li G, et al. Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity. Cell Death Dis. 2024;15:36.PubMed  PubMed Central  Google Scholar Leon-Rodriguez A, Grondona JM, Marin-Wong S, Lopez-Aranda MF, Lopez-Avalos MD. Long-term reprogramming of primed microglia after moderate inhibition of CSF1R signaling. Glia. 2025;73:175–95.Christ A, Gunther P, Lauterbach MAR, Duewell P, Biswas D, Pelka K, et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell. 2018;172:162–75.e114.PubMed  PubMed Central  Google Scholar Fu J, Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol. 2023;41:301–16.PubMed  PubMed Central  Google Scholar Barichello T, Generoso JS, Goularte JA, Collodel A, Pitcher MR, Simoes LR, et al. Does infection-induced immune activation contribute to dementia? Aging Dis. 2015;6:342–8.PubMed  PubMed Central  Google Scholar Yao H, Zhang D, Yu H, Yuan H, Shen H, Lan X, et al. Gut microbiota regulates chronic ethanol exposure-induced depressive-like behavior through hippocampal NLRP3-mediated neuroinflammation. Mol Psychiatry. 2023;28:919–30.PubMed  Google Scholar Wang H, He Y, Sun Z, Ren S, Liu M, Wang G, et al. Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression. J Neuroinflammation. 2022;19:132.PubMed  PubMed Central  Google Scholar Maes M, Almulla AF, You Z, Zhang Y. Neuroimmune, metabolic and oxidative stress pathways in major depressive disorder. Nat Rev Neurol. 2025;21:473–89.Dong Z, Hou L, Luo W, Pan LH, Li X, Tan HP, et al. Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis. Eur Heart J. 2024;45:669–84.PubMed  Google Scholar Liu MY, Yin CY, Zhu LJ, Zhu XH, Xu C, Luo CX, et al. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat Protoc. 2018;13:1686–98.PubMed  Google Scholar Pan RY, He L, Zhang J, Liu X, Liao Y, Gao J, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab. 2022;34:634–48.e636.PubMed  Google Scholar Zhang J, Rong P, Zhang L, He H, Zhou T, Fan Y, et al. IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis. Sci Adv. 2021;7:eabb9888.PubMed  PubMed Central  Google Scholar Remus JL, Jamison D, Johnson JD. An animal model of recurrent depression: Sensitized depression-like behavior when rats are re-exposed to chronic mild stress. Brain Behav Immun. 2013;32:e4-e5.Alves ND, Correia JS, Patricio P, Mateus-Pinheiro A, Machado-Santos AR, Loureiro-Campos E, et al. Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression. Transl Psychiatry. 2017;7:e1058.PubMed  PubMed Central  Google Scholar Li B, Yang W, Ge T, Wang Y, Cui R. Stress induced microglial activation contributes to depression. Pharmacol Res. 2022;179:106145.PubMed  Google Scholar Jinqiang Z, Hui H, Yan Q, Tao Z, Haili H, Saini Y, et al. Priming of microglia with IFN-γ impairs adult hippocampal neurogenesis and leads to depression-like behaviors and cognitive defects. Glia. 2020;68:2674–92.Google Scholar Cheong JG, Ravishankar A, Sharma S, Parkhurst CN, Grassmann SA, Wingert CK, et al. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors. Cell. 2023;186:3882–902.e3824.PubMed  PubMed Central  Google Scholar Pimenova AA, Herbinet M, Gupta I, Machlovi SI, Bowles KR, Marcora E, et al. Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response. Neurobiol Dis. 2021;148:105217.PubMed  Google Scholar Cao P, Chen C, Liu A, Shan Q, Zhu X, Jia C, et al. Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines. Neuron. 2021;109:2573–89.e2579.PubMed  Google Scholar Wang H, Helin K. Roles of H3K4 methylation in biology and disease. Trends Cell Biol. 2024;35:115–28.Cao Q, Wang W, Williams JB, Yang F, Wang ZJ, Yan Z. Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease. Sci Adv. 2020;6:eabc8096.PubMed  PubMed Central  Google Scholar Li S, Fang Y, Zhang Y, Song M, Zhang X, Ding X, et al. Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice. Cell Rep. 2022;41:111532.PubMed  Google Scholar He H, Xie X, Zhang J, Mo L, Kang X, Zhang Y, et al. Patchouli alcohol ameliorates depression-like behaviors through inhibiting NLRP3-mediated neuroinflammation in male stress-exposed mice. J Affect Disord. 2023;326:120–31.PubMed  Google Scholar Wu A, Zhang J. Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis. J Neuroinflammation. 2023;20:283.PubMed  PubMed Central  Google Scholar Lemke H, Klute H, Skupski J, Thiel K, Waltemate L, Winter A, et al. Brain structural correlates of recurrence following the first episode in patients with major depressive disorder. Transl Psychiatry. 2022;12:349.PubMed  PubMed Central  Google Scholar Netea MG, Schlitzer A, Placek K, Joosten LAB, Schultze JL. Innate and adaptive immune memory: an evolutionary continuum in the host’s response to pathogens. Cell Host Microbe. 2019;25:13–26.PubMed  Google Scholar Dong H, Zhang X, Duan Y, He Y, Zhao J, Wang Z, et al. Hypoxia inducible factor-1alpha regulates microglial innate immune memory and the pathology of Parkinson’s disease. J Neuroinflammation. 2024;21:80.PubMed  PubMed Central  Google Scholar Jamieson AM, Pasman L, Yu S, Gamradt P, Homer RJ, Decker T, et al. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science. 2013;340:1230–4.PubMed  PubMed Central  Google Scholar Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, et al. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol. 2021;22:2–6.PubMed  PubMed Central  Google Scholar Salam AP, Borsini A, Zunszain PA. Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders. Mol Psychiatry. 2018;23:170–6.PubMed  Google Scholar Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345:1251086.PubMed  PubMed Central  Google Scholar Cruceanu C, Alda M, Nagy C, Freemantle E, Rouleau GA, Turecki G. H3K4 tri-methylation in synapsin genes leads to different expression patterns in bipolar disorder and major depression. Int J Neuropsychopharmacol. 2013;16:289–99.PubMed  Google Scholar Li R, Zhao H, Huang X, Zhang J, Bai R, Zhuang L, et al. Super-enhancer RNA m(6)A promotes local chromatin accessibility and oncogene transcription in pancreatic ductal adenocarcinoma. Nat Genet. 2023;55:2224–34.PubMed  Google Scholar Li S. Benefits of physical exercise on Alzheimer’s disease: an epigenetic view. Ageing and Neurodegenerative Diseases. 2023;3:6.Google Scholar Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50–59.PubMed  Google Scholar Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5.PubMed  Google Scholar Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 2018;18:e27.PubMed  PubMed Central  Google Scholar Gong T, Liu L, Jiang W, Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020;20:95–112.PubMed  Google Scholar Brinholi FF, Vasupanrajit A, Semeao LO, Michelin AP, Matsumoto AK, Almulla AF, et al. Increased malondialdehyde and nitric oxide formation, lowered total radical trapping capacity coupled with psychological stressors are strongly associated with the phenome of first-episode mild depression in undergraduate students. Neuroscience. 2024;554:52–62.PubMed  Google Scholar Monroe SM, Harkness KL. Major depression and its recurrences: life course matters. Annu Rev Clin Psychol. 2022;18:329–57.PubMed  Google Scholar Monroe SM, Harkness KL. Life stress, the “kindling” hypothesis, and the recurrence of depression: considerations from a life stress perspective. Psychol Rev. 2005;112:417–45.PubMed  Google Scholar Ilgen MA, Hutchison KE. A history of major depressive disorder and the response to stress. J Affect Disord. 2005;86:143–50.PubMed  Google Scholar Han N, Heublein S, Jeschke U, Kuhn C, Hester A, Czogalla B, et al. The G-protein-coupled estrogen receptor (GPER) regulates trimethylation of histone H3 at lysine 4 and represses migration and proliferation of ovarian cancer cells in vitro. Cells. 2021;10:619.PubMed  PubMed Central  Google Scholar Wen X, Xiao Y, Xiao H, Tan X, Wu B, Li Z, et al. Bisphenol S induces brown adipose tissue whitening and aggravates diet-induced obesity in an estrogen-dependent manner. Cell Rep. 2023;42:113504.PubMed  Google Scholar Peng S, Su P, Liu L, Li Z, Liu Y, Tian L, et al. Formononetin ameliorates depression-like behaviors through rebalancing microglia M1/M2 polarization and inhibiting NLRP3 inflammasome: involvement of activating PPARalpha-mediated autophagy. Mol Med. 2025;31:153.PubMed  PubMed Central  Google Scholar Lammerding L, Slowik A, Johann S, Beyer C, Zendedel A. Poststroke inflammasome expression and regulation in the peri-infarct area by gonadal steroids after transient focal ischemia in the rat brain. Neuroendocrinology. 2016;103:460–75.PubMed  Google Scholar