Journal of Neuroimmune Pharmacology

, Volume 13, Issue 3, pp 309–329 | Cite as

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

  • Yosra Bedoui
  • Jim W. NealEmail author
  • Philippe GasqueEmail author


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.


Innate immunity Brain Neuroinflammation Tissue tolerance Tissue resilience Neuro-immune regulators NIREG Don’t eat me signals Microglia 


fibrillary beta amyloid


adenosine triphosphate


apoptotic- cell- associated molecular patterns


alzheimer’s disease


amyloid β precursor protein


blood brain barrier


Bcl-2 adenovirus E1B 19-kDa interacting protein 3




central nervous system


C pathway


C receptors


complement NIREGs


complement receptor-related protein y


cerebro spinal fluid


decay accelerating factor


danger associated molecular patterns


dendritic cell


downstream tyrosine kinase 2


experimental autoimmune encephalitis


epidermal growth factor


endoplasmic reticulum


factor H

Gas 6

growth arrest specific 6


Glioblastoma multiforme


glioma stem like cells


glycosyl phosphatidyl inositol


high mobilty group box protein 1


heat shock proteins




immunoglobulin superfamily


immune receptor tyrosine based activation motif


immune receptor tyrosine based inhibition motif


janus kinase




membrane attack complex


p38 mitogen activated kinase


mannose binding lectin


membrane cofactor protein


milk fat globule epidermal growth factor 8


matrix metalloproteinase


multiple sclerosis


major histocompatibility complex


macrophage mannose receptor


nerve growth factor


N-methyl-D-aspartate receptor


neuroimmune regulatory protein


natural killer


nucleotide-binding oligomerization domain-like receptors


nucleotide binding leucine rich protein 3


nitric oxide




plasminogen activator inhibitor


pathogen-associated molecular patterns


protease activated receptor


pigment epithelium derived factor


phosphatidylinositol 3-kinase


protease glial derived nexin −1


peroxisome proliferator activated receptor gamma


protein S


pattern recognition receptor


phosphatidyl serine




receptor for advanced glycated end products


Ras p21 protein activator 1


reactive oxygen species


self associated molecular patterns


serine protease inhibitors


sialic acid binding immunoglobulin like lectins


signal regulatory protein


SH2 domain-containing phosphatase


suppressor of cytokine signaling proteins


scavenger receptor


single stranded DNA


signal transducers and activators of transcription




transforming growth factor


tight junctions


toll like receptors




tumor necrosis factor


tissue plasminogen


triggering receptor of myeloid cells


T regulatory cells




unfolded protein response


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© Springer Science+Business Media, LLC, part of Springer Nature 2018
corrected publication June/2018

Authors and Affiliations

  1. 1.Université de la Réunion, CRNS 9192, INSERM U1187, IRD249, Unité Mixte Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Plateforme Technologique CYROISaint –ClotildeFrance
  2. 2.Infection and ImmunityCardiff UniversityCardiffUK
  3. 3.Laboratoire de biologie, secteur laboratoire d’immunologie Clinique et expérimentale ZOI, LICE-OI, CHU Felix Guyon BellepierreSt DenisFrance

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