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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. Neal
  • Philippe Gasque
INVITED REVIEW

Abstract

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.

Keywords

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

Abbreviations

fibrillary beta amyloid

ATP

adenosine triphosphate

ACAMPS

apoptotic- cell- associated molecular patterns

AD

alzheimer’s disease

APP

amyloid β precursor protein

BBB

blood brain barrier

BNIP3

Bcl-2 adenovirus E1B 19-kDa interacting protein 3

C

complement

CNS

central nervous system

CP

C pathway

CR

C receptors

CREGs

complement NIREGs

CRRY

complement receptor-related protein y

CSF

cerebro spinal fluid

DAF

decay accelerating factor

DAMPs

danger associated molecular patterns

DC

dendritic cell

Dok2

downstream tyrosine kinase 2

EAE

experimental autoimmune encephalitis

EGF

epidermal growth factor

ER

endoplasmic reticulum

FH

factor H

Gas 6

growth arrest specific 6

GBM

Glioblastoma multiforme

GSLC

glioma stem like cells

GPI

glycosyl phosphatidyl inositol

HMGB1

high mobilty group box protein 1

HSP

heat shock proteins

IFN

interferon

IgSF

immunoglobulin superfamily

ITAM

immune receptor tyrosine based activation motif

ITIM

immune receptor tyrosine based inhibition motif

JAK

janus kinase

LPS

lipopolysaccharide

MAC

membrane attack complex

MAPK

p38 mitogen activated kinase

MBL

mannose binding lectin

MCP

membrane cofactor protein

MF-EGF 8

milk fat globule epidermal growth factor 8

MMP

matrix metalloproteinase

MS

multiple sclerosis

MHC

major histocompatibility complex

MMR

macrophage mannose receptor

NGF

nerve growth factor

NMDA

N-methyl-D-aspartate receptor

NIREG

neuroimmune regulatory protein

NK

natural killer

NLR

nucleotide-binding oligomerization domain-like receptors

NLRP3

nucleotide binding leucine rich protein 3

NO

nitric oxide

NSP

neuroserpin

PAI

plasminogen activator inhibitor

PAMPs

pathogen-associated molecular patterns

PAR

protease activated receptor

PEDF

pigment epithelium derived factor

PI3-K

phosphatidylinositol 3-kinase

PN-1

protease glial derived nexin −1

PPAR-γ

peroxisome proliferator activated receptor gamma

PROS1

protein S

PRR

pattern recognition receptor

PS

phosphatidyl serine

PT

prothrombin

RAGE

receptor for advanced glycated end products

Ras GAP

Ras p21 protein activator 1

ROS

reactive oxygen species

SAMPs

self associated molecular patterns

Serpins

serine protease inhibitors

Siglecs

sialic acid binding immunoglobulin like lectins

SIRP

signal regulatory protein

SHP

SH2 domain-containing phosphatase

SOCS

suppressor of cytokine signaling proteins

SR

scavenger receptor

ssDNA

single stranded DNA

STAT

signal transducers and activators of transcription

TAM

TYRO3,Axl,Mer

TGF

transforming growth factor

TJ

tight junctions

TLR

toll like receptors

TM

thrombomodulin

TNF

tumor necrosis factor

tPA

tissue plasminogen

TREM

triggering receptor of myeloid cells

Tregs

T regulatory cells

TSP

thrombospondins

UPR

unfolded protein response

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Copyright information

© 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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