The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560029, India.
Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jul 1;44:301-11. doi: 10.1016/j.pnpbp.2013.04.001. Epub 2013 Apr 12.
Mounting evidence indicates that immune activation and/or immuno-inflammatory reactions during neurodevelopment apparently contribute to the pathogenesis and progression of schizophrenia. One of the important environmental factors that is known to trigger immune activation/inflammatory responses during early pregnancy is prenatal infection. Recent understanding from animal studies suggests that prenatal infection induced maternal immune activation (MIA)/inflammation in congruence with oxidative/nitrosative stress can lead to neurodevelopmental damage and behavioral abnormalities in the offspring. Although the underlying precise mechanistic processes of MIA/inflammation are yet to be completely elucidated, it is being increasingly recognized that Toll-like receptors (TLRs) that form the first line of defense against invading microorganisms could participate in the prenatal infection induced immune insults. Interestingly, some of the TLRs, especially TLR3 and TLR4 that modulate neurodevelopment, neuronal survival and neuronal plasticity by regulating the neuro-immune cross-talk in the developing and adult brain could also be affected by prenatal infection. Importantly, sustained activation of TLR3/TLR4 due to environmental factors including infection and stress has been found to generate excessive reactive oxygen species (ROS)/reactive nitrogen species (RNS) as well as pro-inflammatory mediators during embryogenesis, which result into neuronal damage by necrosis/apoptosis. In recent times, ROS/RNS and immuno-inflammatory mediators are being increasingly linked to progressive brain changes in schizophrenia. Although a significant role of TLR3/TLR4 in neurodegeneration is gaining certainty, their importance in establishing a causal link between prenatal infection and immuno-inflammatory, oxidative and nitrosative stress (IO&NS) responses and influence on adult presentation of schizophrenia is yet to be ascertained. We review here the current knowledge generated from the animal and human studies on the role of TLRs in schizophrenia and finally propose the "TRIPS Hypothesis" (Toll-like receptors in immuno-inflammatory pathogenesis) to elucidate the underlying mechanism(s) of TLR-mediated risk of schizophrenia. Considering the established role of TLR3 and TLR4 in antiviral and antibacterial responses respectively, we believe that in some cases of schizophrenia where IO&NS responses are evident, prenatal infection might lead to neuroprogressive changes in a TLR3/TLR4-dependent way.
越来越多的证据表明，神经发育过程中的免疫激活和/或免疫炎症反应显然有助于精神分裂症的发病和进展。已知在妊娠早期引发免疫激活/炎症的一个重要环境因素是产前感染。来自动物研究的最新认识表明，产前感染诱导的母体免疫激活（MIA）/炎症与氧化/硝化应激一致，可导致后代的神经发育损伤和行为异常。尽管 MIA/炎症的确切机制过程尚未完全阐明，但人们越来越认识到，作为抵御入侵微生物的第一道防线的 Toll 样受体（TLR）可能参与产前感染引起的免疫损伤。有趣的是，一些 TLR，特别是调节神经发育、神经元存活和神经元可塑性的 TLR3 和 TLR4，也可以通过调节发育中和成年大脑中的神经免疫交叉对话而受到产前感染的影响。重要的是，由于感染和应激等环境因素，TLR3/TLR4 的持续激活已被发现会在胚胎发生过程中产生过多的活性氧（ROS）/活性氮（RNS）和促炎介质，从而导致神经元坏死/凋亡损伤。最近，ROS/RNS 和免疫炎症介质与精神分裂症的进行性脑改变越来越相关。虽然 TLR3/TLR4 在神经退行性变中的作用越来越确定，但它们在确定产前感染与免疫炎症、氧化和硝化应激（IO&NS）反应之间的因果关系以及对精神分裂症成人表现的影响方面的重要性尚未确定。我们在这里回顾了来自动物和人类研究的关于 TLR 在精神分裂症中的作用的现有知识，并最终提出了“TRIPS 假说”（免疫炎症发病机制中的 Toll 样受体）来阐明 TLR 介导的精神分裂症风险的潜在机制。考虑到 TLR3 和 TLR4 在抗病毒和抗菌反应中的作用分别得到确立，我们认为在某些情况下 IO&NS 反应明显，产前感染可能以 TLR3/TLR4 依赖的方式导致神经进行性变化。
