Université de la Réunion, CRNS 9192, INSERM U1187, IRD249, Unité Mixte Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Plateforme Technologique CYROI, Saint -Clotilde, La Réunion, France.
Infection and Immunity, Cardiff University, Henry Wellcome Building, Cardiff, CF14 4XN, UK.
J Neuroimmune Pharmacol. 2018 Sep;13(3):309-329. doi: 10.1007/s11481-018-9793-6. Epub 2018 Jun 16.
An effective protective inflammatory response in the brain is crucial for the clearance of pathogens (e.g. microbes, amyloid fibrils, prion) and should be closely regulated. However, the CNS seems to have limited tissue resilience to withstand the detrimental effects of uncontrolled inflammation compromising functional recovery and tissue repair. Newly described neuro-immune-regulators (NIREGs) are functionally related proteins regulating the severity and duration of the host inflammatory response. NIREGs such as CD200, CD47 and CX3CL1 are vital for increasing tissue resilience and are constitutively expressed by neurons. The interaction with co-receptors (CD200R, CD172a, CX3CR1) will maintain microglia in the resting phenotype, directing aggressive microglia phenotype and limiting bystander injuries. Neurons can also express many of the complement NIREGs (CD55, CD46, CD59 and factor H). Neurons and glia also express suppressor of cytokine signaling proteins (SOCS) down regulating janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway and to lead to the polarization of microglia towards anti-inflammatory phenotype. Other NIREGs such as serine protease inhibitors (serpins) and thrombomodulin (CD141) inhibit neurotoxic systemic coagulation proteins such as thrombin. The unfolded protein response (UPR) detects misfolded proteins and other stressors to prevent irreversible cell injury. Microglial pattern recognition receptors (PRR) (TREM-2, CR3, FcγR) are important to clear apoptotic cells and cellular debris but in non-phlogystic manner through inhibitory signaling pathways. The TYRO3, Axl, Mer (TAM) tyrosine receptor kinases activated by Gas 6 and PROS1 regulate inflammation by inhibiting Toll like receptors (TLR) /JAK-STAT activation and contribute to NIREG's functions.
在大脑中，有效的保护性炎症反应对于清除病原体（例如微生物、淀粉样纤维、朊病毒）至关重要，并且应该受到密切调节。然而，中枢神经系统似乎对不受控制的炎症的有害影响具有有限的组织弹性，这会损害功能恢复和组织修复。新描述的神经免疫调节剂（NIREGs）是功能相关的蛋白质，可调节宿主炎症反应的严重程度和持续时间。CD200、CD47 和 CX3CL1 等 NIREGs对于增加组织弹性至关重要，并且由神经元组成性表达。与共受体（CD200R、CD172a、CX3CR1）的相互作用将使小胶质细胞保持静止表型，指导侵袭性小胶质细胞表型，并限制旁观者损伤。神经元还可以表达许多补体 NIREGs（CD55、CD46、CD59 和因子 H）。神经元和神经胶质细胞也表达细胞因子信号转导抑制蛋白（SOCS），下调 Janus 激酶信号转导和转录激活因子（JAK/STAT）途径，并导致小胶质细胞向抗炎表型极化。其他 NIREGs，如丝氨酸蛋白酶抑制剂（serpins）和血栓调节蛋白（CD141），抑制神经毒性系统性凝血蛋白，如凝血酶。未折叠蛋白反应（UPR）检测错误折叠的蛋白质和其他应激源，以防止不可逆的细胞损伤。小胶质细胞模式识别受体（PRR）（TREM-2、CR3、FcγR）对于清除凋亡细胞和细胞碎片非常重要，但通过抑制性信号通路以非炎症方式进行。激活 TYRO3、AXL、Mer（TAM）酪氨酸受体激酶的 Gas 6 和 PROS1 通过抑制 Toll 样受体（TLR）/JAK-STAT 激活来调节炎症，并有助于 NIREG 的功能。
