As tissue-resident macrophages of the brain, microglia are increasingly considered as cellular targets for therapeutical intervention. Innate immune responses in particular have been implicated in central nervous system (CNS) infections, neuro-oncology, neuroinflammatory and neurodegenerative diseases. We here review the impact of ‘nature and nurture’ on microglial innate immune responses and summarize documented tissue-specific adaptations. Overall, such adaptations are associated with regulatory processes rather than with overt differences in the expressed repertoire of activating receptors of different tissue-resident macrophages. Microglial responses are characterized by slower kinetics, by a more persistent nature and by a differential usage of downstream enzymes and accessory receptors. We further consider factors like aging, previous exposure to inflammatory stimuli, and differences in the microenvironment that can modulate innate immune responses. The long-life span of microglia in the metabolically active CNS renders them susceptible to the phenomenon of ‘inflammaging’, and major challenges lie in the unraveling of the factors that underlie age-related alterations in microglial behavior.

作为大脑的组织驻留巨噬细胞，小胶质细胞越来越多地被认为是治疗干预的细胞靶点。先天免疫反应尤其与中枢神经系统 (CNS) 感染、神经肿瘤学、神经炎症和神经退行性疾病有关。我们在这里回顾了“先天和后天”对小胶质细胞先天免疫反应的影响，并总结了记录在案的组织特异性适应。总的来说，这种适应与调节过程有关，而不是与不同组织驻留巨噬细胞的激活受体表达谱的明显差异有关。小胶质细胞反应的特点是动力学较慢、性质更持久以及下游酶和辅助受体的不同使用。我们进一步考虑老化等因素，先前暴露于炎症刺激，以及可以调节先天免疫反应的微环境差异。代谢活跃的中枢神经系统中小胶质细胞的长寿命使它们容易受到“炎症”现象的影响，主要挑战在于解开与年龄相关的小胶质细胞行为改变的基础因素。