The Neuro-Immune-Regulators (NIREGs) Promote Tissue Resilience; a Vital Component of the Host’s Defense Strategy against Neuroinflammation

An effective protective inflammatory response in the brain is crucial for the clearance of pathogens (e.g. microbes, amyloid fibrils, prionSC) 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.