Defence Institute of Physiology and Allied Sciences, Delhi 110054, India.
Defence Research and Development Organisation (DRDO), New Delhi 110011, India.
J Neuroimmunol. 2021 Aug 15;357:577625. doi: 10.1016/j.jneuroim.2021.577625. Epub 2021 Jun 5.
Innate immune memory, a crucial mechanism of epigenetically mediated myeloid cell plasticity, alters subsequent immune responses majorly by two types of immunological imprinting, training, and tolerance. Recent pioneer studies provided proof-of-principle for generation of both types of innate immune memory in brain macrophage, microglial cells. This novel study was designed to investigate whether the pattern of immune response generation, induced by peripheral administration of recombinant alarmin HMGB1, alone and in combination with other recombinant cytokines, is affected by prior exposure. The experimental outcomes revealed that full length recombinant HMGB1 exposure for seven consecutive days exhibit inflammatory response as evidenced by enhanced expression of inflammatory biomarkers and neurodegeneration. In contrary, combined doses of HMGB1 and IL-1β, for three and seven consecutive days, exhibited lower inflammatory state compared to its alone HMGB1 counterpart. The immune tolerance state was evident by microglial polarization towards non-reactive M2 state, lower astrocyte activation, epigenetic reprogramming, and decreased neurodegeneration. This is the first demonstration that HMGB1 and IL-1β priming can differentially affect inflammation in the brain when a host is confronted with a second, third stimulus or so on. The findings were further validated by suppressing major regulators of epigenetic reprogramming, by intranasal delivery of specific siRNAs targeting those regulators. These results may provide new evidence for the involvement of recombinant endogenous cytokine induced generation of innate immune tolerance within microglial cells and indicated the possible potential role in mediating cognitive and behavioural alterations during inflammatory diseases.
先天免疫记忆是一种由表观遗传介导的髓样细胞可塑性的关键机制，它主要通过两种免疫印迹、训练和耐受来改变随后的免疫反应。最近的先驱研究为脑巨噬细胞、小胶质细胞中这两种类型的先天免疫记忆的产生提供了原理证明。这项新研究旨在探讨外周给予重组警报素 HMGB1 及其与其他重组细胞因子联合应用是否会影响免疫反应的产生模式。实验结果表明，全长重组 HMGB1 连续 7 天暴露表现出炎症反应，表现为炎症生物标志物表达增强和神经退行性变。相反，HMGB1 和 IL-1β 的联合剂量连续 3 天和 7 天给药与单独 HMGB1 相比表现出较低的炎症状态。免疫耐受状态表现为小胶质细胞向非反应性 M2 状态极化，星形胶质细胞激活减少，表观遗传重编程降低，神经退行性变减少。这是第一个证明 HMGB1 和 IL-1β 启动可以在宿主面临第二次、第三次刺激等时，以不同的方式影响大脑中的炎症的证据。通过鼻内递送针对这些调节剂的特定 siRNA 来抑制表观遗传重编程的主要调节剂，进一步验证了这些发现。这些结果可能为内源性细胞因子重组诱导小胶质细胞中先天免疫耐受的产生提供新的证据，并表明其在炎症性疾病期间介导认知和行为改变的可能潜在作用。
