Richards Christy M, McRae Seamus A, Ranger Athena L, Klegeris Andis
Department of Biology, University of British Columbia Okanagan Campus, Kelowna V1V 1V7, BC, Canada.
Rev Neurosci. 2022 Nov 11;34(5):533-558. doi: 10.1515/revneuro-2022-0091. Print 2023 Jul 26.
The four core histones H2A, H2B, H3, H4, and the linker histone H1 primarily bind DNA and regulate gene expression within the nucleus. Evidence collected mainly from the peripheral tissues illustrates that histones can be released into the extracellular space by activated or damaged cells. In this article, we first summarize the innate immune-modulatory properties of extracellular histones and histone-containing complexes, such as nucleosomes, and neutrophil extracellular traps (NETs), described in peripheral tissues. There, histones act as damage-associated molecular patterns (DAMPs), which are a class of endogenous molecules that trigger immune responses by interacting directly with the cellular membranes and activating pattern recognition receptors (PRRs), such as toll-like receptors (TLR) 2, 4, 9 and the receptor for advanced glycation end-products (RAGE). We then focus on the available evidence implicating extracellular histones as DAMPs of the central nervous system (CNS). It is becoming evident that histones are present in the brain parenchyma after crossing the blood-brain barrier (BBB) or being released by several types of brain cells, including neurons, microglia, and astrocytes. However, studies on the DAMP-like effects of histones on CNS cells are limited. For example, TLR4 is the only known molecular target of CNS extracellular histones and their interactions with other PRRs expressed by brain cells have not been observed. Nevertheless, extracellular histones are implicated in the pathogenesis of a variety of neurological disorders characterized by sterile neuroinflammation; therefore, detailed studies on the role these proteins and their complexes play in these pathologies could identify novel therapeutic targets.
四种核心组蛋白H2A、H2B、H3、H4以及连接组蛋白H1主要与DNA结合并调节细胞核内的基因表达。主要从外周组织收集的证据表明，组蛋白可由活化或受损细胞释放到细胞外空间。在本文中，我们首先总结外周组织中描述的细胞外组蛋白和含组蛋白复合物（如核小体和中性粒细胞胞外陷阱（NETs））的固有免疫调节特性。在那里，组蛋白作为损伤相关分子模式（DAMPs），这是一类内源性分子，通过直接与细胞膜相互作用并激活模式识别受体（PRRs）（如Toll样受体（TLR）2、4、9和晚期糖基化终产物受体（RAGE））来触发免疫反应。然后，我们关注表明细胞外组蛋白作为中枢神经系统（CNS）的DAMPs的现有证据。越来越明显的是，组蛋白在穿过血脑屏障（BBB）后或由包括神经元、小胶质细胞和星形胶质细胞在内的几种类型的脑细胞释放后存在于脑实质中。然而，关于组蛋白对CNS细胞的类DAMP效应的研究有限。例如，TLR4是CNS细胞外组蛋白唯一已知的分子靶点，尚未观察到它们与脑细胞表达的其他PRRs的相互作用。尽管如此，细胞外组蛋白与以无菌性神经炎症为特征的多种神经疾病的发病机制有关；因此，对这些蛋白质及其复合物在这些病理过程中所起作用的详细研究可能会确定新的治疗靶点。
