Key Concepts in Neuroimmunology,

a dialogue between Philosophers and Scientists

Which cells are the immune cells of the brain?

Agnès Nadjar NutriNeuro, UMR INRA 1286

University of Bordeaux, France

MICROGLIA:THEBRAININNATEIMMUNESYSTEM

BRAIN IMMUNESYSTEM

THECNS:ASITEOFLIMITEDIMMUNESURVEILLANCE

BBB

MICROGLIA:THERESIDENTIMMUNECELLSOFTHEBRAIN(Ransohoff,2016)

(Rio-HortegaPdel.1932.Volume2.EditedbyWPenfield,Hoeber,NewYork,pp.482-534)

PIODELRIOHORTEGA(1882-1945)

√FIRSTCALLED“MICROGLIA”AROUND1920√BASEDONNISSLSTAINING

THEDISCOVERYOFMICROGLIALCELLS

SANTIAGORAMONYCAJAL(1852-1934)

1.Microgliaenterthebrainduringearlydevelopment.2.Theseinvadingcellshaveamoeboidmorphologyandareofmesodermal

origin.3.TheyusevesselsandwhitemaAertractsasguidingstructuresfor

migraBonandenterallbrainregions.4.Theytransformintoabranched,ramifiedmorphologicalphenotypeinthemorematurebrain(knowntodayastheresBngmicroglia).

5.Inthematurebrain,theyarefoundalmostevenlydispersedthroughoutthecentralnervoussystemanddisplayliAlevariaBon.

6.Eachcellseemstooccupyadefinedterritory.7.ALerapathologicalevent,thesecellsundergoatransformaBon.8.Transformedcellsacquireamoeboidmorphologysimilartotheone

observedearlyindevelopment.9.Thesecellshavethecapacitytomigrate,proliferateandphagocytose.

S`llvalidtoday4

ORIGINALSTATEMENTSFROMHORTEGA

CNSIMMUNEREGULATION:THECLASSICALVIEW

HEALTHYTISSUE LARGEINSULTSMALLLOCALDAMAGE

(HanischandKebenmann,NatureNeuroscience,2007)

THEYINANDYANGOFMICROGLIALACTIVATION

(Gentleman, Neuropathology and Applied Neurology, 2013; Patel et al., Int J Physiol Patho Pharm, 2013; Aguzzi et al., Science, 2013)

PHENOTYPICPLASTICITYOFMICROGLIA

EACHPATHOLOGICALSITUATIONISASSOCIATEDTOAUNIQUEPHENOTYPICSHIFT

(Perry et al., Nature Reviews Neurology, 2010)

MICROGLIAISNOTJUSTANIMMUNECELL

(Ginhouxetal.,Fron`ersinCellularNeuroscience,2013)

BBBForma`on

Prolifera`onEarlyInvasion

9

MICROGLIAENTERSTHEBRAINVERYEARLYDURINGDEVELOPMENT

MICROGLIAISINVOLVEDINCNSDEVELOPMENT

(FrostandSchafer,TrendsinCellBiology,2016)

MICROGLIA:FARFROMBEING«DORMANTSOLDIER»

SENTINELS

(Nimmerjahnetal.,Science,2005)

12

MICROGLIAMAKESCONTACTSWITHNEURONS

(Wakeetal.,JournalofNeuroscience,2009;Kebenmannetal.,2012)

MICROGLIANEVERWALKSALONE

THEBRAINIMMUNESYSTEMANATOMYMATTERS

(Engelhardt et al., Nature Immunology, 2016)

CNS-ASSOCIATEDLEUKOCYTEDIVERSITYINTHESTEADY-STATE

(Mrdjen et al., Immunity 2018)

CNS-ASSOCIATEDLEUKOCYTEDIVERSITYINTHESTEADY-STATE

(Mrdjen et al., Immunity 2018)

BORDER-ASSOCIATEDMACROPHAGES(BAM)

√DIFFERENTLOCATIONSWITHINTHECNS

(Mrdjen et al., Immunity 2018)

√4SUBSETSOFBAMS.

DENDRITICCELLS

(Mrdjen et al., Immunity 2018)

LEUKOCYTESTURNOVER

(Mrdjen et al., Immunity 2018)

AGINGCAUSESANALTEREDCNSIMMUNELANDSCAPE…

(Mrdjen et al., Immunity 2018)

…ANDASUBSETOFREACTIVEMICROGLIAEMERGES

(Mrdjen et al., Immunity 2018)

AUTOIMMUNENEUROINFLAMMATIONEAEMODEL

(Mrdjen et al., Immunity 2018)

CONCLUSIONTHECNSIMMUNESYSTEM:NEWCONCEPT

NEUROINFLAMMATION

STATE1

STATE2

STATE3

√WHATISTHEBRAINIMMUNESYSTEM?√WHATISITSROLE?STEADY-STATE,PATHOLOGY?√HOWDOLEUKOCYTESCOORDINATETHEIRRESPONSEINTHECNS√WHATISTHEROLEOFMICROGLIAUNDERIMMUNEACTIVATION?√INTERACTIONWITHPERIPHERALIMMUNESYSTEM?√ISTHEREAFRONTIERBETWEENPERIPHERALANDCENTRALIMMUNE

SYSTEMS?ROLEOFTHATFRONTIERINIMMUNERESPONSE

CONCLUSIONTHECNSIMMUNESYSTEM:NEWCONCEPT

Thank you for your attention