Holland Seth D, Ramer Matt S
International Collaboration on Repair Discoveries, The University of British Columbia, Vancouver, BC, Canada.
Front Mol Neurosci. 2023 Mar 23;16:1150296. doi: 10.3389/fnmol.2023.1150296. eCollection 2023.
Activating Transcription Factor 3 (ATF3) is upregulated in reaction to several cellular stressors found in a wide range of pathological conditions to coordinate a transcriptional response. ATF3 was first implicated in the transcriptional reaction to axotomy when its massive upregulation was measured in sensory and motor neuron cell bodies following peripheral nerve injury. It has since been shown to be critical for successful axon regeneration in the peripheral nervous system and a promising target to mitigate regenerative failure in the central nervous system. However, much of the research to date has focused on ATF3's function in neurons, leaving the expression, function, and therapeutic potential of ATF3 in glia largely unexplored. In the immunology literature ATF3 is seen as a master regulator of the innate immune system. Specifically, in macrophages following pathogen or damage associated molecular pattern receptor activation and subsequent cytokine release, ATF3 upregulation abrogates the inflammatory response. Importantly, ATF3 upregulation is not exclusively due to cellular stress exposure but has been achieved by the administration of several small molecules. In the central nervous system, microglia represent the resident macrophage population and are therefore of immediate interest with respect to ATF3 induction. It is our perspective that the potential of inducing ATF3 expression to dampen inflammatory microglial phenotype represents an unexplored therapeutic target and may have synergistic benefits when paired with concomitant neuronal ATF3 upregulation. This would be of particular benefit in pathologies that involve both detrimental inflammation and neuronal damage including spinal cord injury, multiple sclerosis, and stroke.
激活转录因子3（ATF3）在多种病理状况下的几种细胞应激源反应中上调，以协调转录反应。ATF3首次与轴突切断后的转录反应相关，当时在周围神经损伤后，感觉和运动神经元细胞体中检测到其大量上调。此后，它已被证明对周围神经系统中轴突的成功再生至关重要，并且是减轻中枢神经系统再生失败的一个有前景的靶点。然而，迄今为止的许多研究都集中在ATF3在神经元中的功能，而ATF3在神经胶质细胞中的表达、功能和治疗潜力在很大程度上尚未得到探索。在免疫学文献中，ATF3被视为先天免疫系统的主要调节因子。具体而言，在病原体或损伤相关分子模式受体激活以及随后细胞因子释放后的巨噬细胞中，ATF3上调可消除炎症反应。重要的是，ATF3上调并非完全由于细胞应激暴露，而是通过施用几种小分子实现的。在中枢神经系统中，小胶质细胞代表常驻巨噬细胞群体，因此就ATF3诱导而言，它们立即引起了人们的兴趣。我们认为，诱导ATF3表达以抑制炎症性小胶质细胞表型的潜力代表了一个未被探索的治疗靶点，并且与同时上调神经元ATF3配对时可能具有协同益处。这在涉及有害炎症和神经元损伤的疾病中，包括脊髓损伤、多发性硬化症和中风，将特别有益。
