Stress-associated immune mechanisms of schizophrenia: the importance of region-specific microglia-neurovascular interaction
Date
2023-11-23
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Abstract
Psühhiaatrilised häired on tööealise elanikkonna hulgas üks peamiseid puude ja surma põhjuseid, suurendades ülemaailmselt märkimisväärset majanduslikku ja tervishoiukoormust. Psühhiaatrilisi häireid võivad esile kutsuda mitmesugused organismi sisemised ja välised tegurid, mis koostoimides mõjutavad aju talitlust ja selle kaudu käitumist. Psühhosotsiaalne stress on laialt tunnustatud skisofreenia tekke ja arengu riskitegur. Teiste bioloogiliste mehhanismide hulgas häirib krooniline stress aju vereringet ja süvendab neuropõletikku. Veresoontega seotud mikrogliia ja monotsüütidest pärinevad makrofaagid on neuropõletiku kõige olulisemateks regulaatoriteks. Selleks, et paremini mõista mikrogliia ja monotsüütide funktsiooni kroonilisest stressist lähtudes, viisime läbi terve rea kliinilisi ja prekliinilisi uuringuid skisofreenia esmasepisoodi (FES) patsientide rühmas, samuti hiirtel, kellel oli rakendatud kroonilist ettearvamatut stressi ja haistesibula purustamisest (OBX) tingitud stressi. Kliiniliste uuringute käigus leidsime, et FES patsientidel, kellel esines kõrgenenud tajutud stressi tase, neil avaldus ajukoore mahu vähenemine otsmikusagaras. Samuti oli neil patsientidel veres vähenenud mitteklassikaliste monotsüütide arv ning mikro-gliia retseptori CSF1R tase. Loommudelites leidsime, et CSF1R-i inhibiitor põhjustas ärevust ja häiris mikrogliia/makrofaagide vaskulaarset seostumist. Peale selle leidsime, et haistesibulas oli rohkesti veresoontega seotud mikrogliiat/ makrofaage ning antud piirkond oli rikastatud rasvhapete metabolismi ja angio¬geneesi geenidega. Lisaks ilmnes, et endogeenseid n-3 PUFA-sid tootvatel fat-1 hiirtel ei avaldu OBX-indutseeritud stressireaktsioonid. Need leiud viitavad sellele, et mikrogliia modulaatorid võivad tänu ajuveresoonkonna efektiivsemale reguleerimisele aidata skisofreenia haigetel stressiga paremini toime tulla. Meie uuringud annavad uudseid teadmisi mikrogliia/monotsüütiliste alampopulatsioonide ja nende kandidaatmolekulide kohta, mis võivad olla kasulikud, et paremini mõista skisofreenia kujunemise ja haigustunnuste püsimise patofüsioloogilisi mehhanisme ja seeläbi töötada välja uusi ravivõimalusi.
Psychiatric disorders are a major source of disability and death for the working-age population and cause considerable economic and healthcare burdens globally. Psychiatric disorders can be caused by miscellaneous intrinsic and extrinsic factors that jointly impact on the brain and behavior. Psychosocial stress is a well-recognized risk factor for onset and development of schizophrenia. Among underlying biological mechanisms, chronic stress disrupts brain blood circulation and exacerbates neuroinflammation. Vascular-associated microglia and monocytes-derived macrophages are the most important regulators for neuroinflammation. To better understand functions of microglia/monocytes in psychiatric disorders through the lens of chronic stress, we performed a series of clinical and preclinical investigations on a cohort of first episode schizophrenia (FES) patients as well as mice undergoing chronic unpredictable stress and olfactory bulbectomy (OBX)-induced stress. In clinical research, we found FES patients suffered with heightened stress, cerebral cortical atrophy, as well as reduced blood nonclassical monocytic abundancy and microglial receptor CSF1R level. In animal models, we found an inhibitor of CSF1R induced anxiety and disrupted vascular association of microglia/macrophages. Besides, we found the olfactory bulb displayed abundant blood vessel-associated microglia/macrophages and was enriched with genes for fatty acid metabolism and angiogenesis. Furthermore, OBX-induced stress responses were rescued in fat-1 mice that produced endogenous n-3 PUFAs. These findings suggest that microglia modulators may benefit stress coping via regulating cerebral blood vasculature in schizophrenia. Our studies hence provide novel knowledge on microglial/monocytic subpopulations and their candidate molecules that may be useful for developing better diagnosis and treatment to tackle psychiatric disorders.
Psychiatric disorders are a major source of disability and death for the working-age population and cause considerable economic and healthcare burdens globally. Psychiatric disorders can be caused by miscellaneous intrinsic and extrinsic factors that jointly impact on the brain and behavior. Psychosocial stress is a well-recognized risk factor for onset and development of schizophrenia. Among underlying biological mechanisms, chronic stress disrupts brain blood circulation and exacerbates neuroinflammation. Vascular-associated microglia and monocytes-derived macrophages are the most important regulators for neuroinflammation. To better understand functions of microglia/monocytes in psychiatric disorders through the lens of chronic stress, we performed a series of clinical and preclinical investigations on a cohort of first episode schizophrenia (FES) patients as well as mice undergoing chronic unpredictable stress and olfactory bulbectomy (OBX)-induced stress. In clinical research, we found FES patients suffered with heightened stress, cerebral cortical atrophy, as well as reduced blood nonclassical monocytic abundancy and microglial receptor CSF1R level. In animal models, we found an inhibitor of CSF1R induced anxiety and disrupted vascular association of microglia/macrophages. Besides, we found the olfactory bulb displayed abundant blood vessel-associated microglia/macrophages and was enriched with genes for fatty acid metabolism and angiogenesis. Furthermore, OBX-induced stress responses were rescued in fat-1 mice that produced endogenous n-3 PUFAs. These findings suggest that microglia modulators may benefit stress coping via regulating cerebral blood vasculature in schizophrenia. Our studies hence provide novel knowledge on microglial/monocytic subpopulations and their candidate molecules that may be useful for developing better diagnosis and treatment to tackle psychiatric disorders.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone
Keywords
schizophrenia, stress, immunity, cerebral cortex, neuroglia, monocytes, metabolomics