Molecular characterization of microglial populations in CX3CR1-GFP mutant mouse line in an LPS induced inflammatory model

Abstract

In English: Microglia are the resident macrophages of the central nervous system (CNS). They constitute the first line of defence within the CNS. Microglia have a crucial role in the development of the central nervous system and also in the mature CNS. Microglia are often attributed a ‘resting’ state under homeostatic conditions. However, studies have shown that resting microglial cells are actively scanning their environment for detection of pathogens. Microglia have a typical ramified shape under homeostatic conditions. Upon detection of external stimuli, they become activated and undergo morphological changes. Activated microglia can produce trophic and anti-inflammatory factors, which serve the purpose of protecting the CNS. However, when microglia are over activated, they release pro inflammatory neurotoxic factors such as superoxide, nitric oxide (NO) and cytokines that contribute to the pathology of neurodegenerative conditions such as Parkinson’s disease (PD). Fractalkine (CX3CL1), a unique chemokine which is the only ligand for its receptor CX3CR1, is expressed by microglia. Several studies have shown that fractalkine acts to protect neurons in vitro in lipopolysaccharide (LPS)-activated microglia by limiting the release of inflammatory factors. The purpose of the thesis was to study the molecular signature of microglial cells of CX3CR1GFP/+ mice and how it is altered by lipopolysaccharide (LPS) administration in an LPS induced inflammatory model. Eesti keeles: Mikrogliia rakud on kesknärvisüsteemis (KNS) elavad makrofaagid ja on KNS-i esimene kaitseliin. Mikrogliial on oluline roll nii kesknärvisüsteemi arengus kui ka täiskasvanud KNS- is. Mikrogliiast rakkudest räägitakse sageli kui homeostaatilistes tingimustes "puhkeolekus" olevatest rakkudest. Tegelikult, uuringud on näidanud, et puhkavad mikrogliia rakud skaneerivad pidevalt KNS-i otsides patogeene. Mikrogliia on homeostaatilistes tingimustes tüüpilise harunenud kujuga, kuid väliste stiimulite avastamisel muutuvad rakud aktiveerituks ja läbivad morfoloogilisi muutusi. Aktiveeritud mikrogliia võib toota troofilisi ja palavikuvastaseid faktoreid, mis töötavad KNS-i kaitsmiseks. Seevastu , kui mikrogliia on üleaktiveeritud, eritavad need rakud neurotoksilisi faktoreid nagu superoksiid, lämmastikoksiid (NO) ja tsütokiinid, mis aitavad kaasa neurodegeneratiivsete seisundite patoloogiale, näiteks Prakinson'i tõbi (PD). Mitmed uuringud on näidanud, et neuronite poolt eskpresserritud fraktalkiin (CX3CL1) - kemokiin, mis on ligand mikrogliia poolt ekspresseeritud retseptorile CX3CR1, piirab põletikuvastaste faktorite vabastamist in vitro lipopolüsahhariid (LPS)- aktiveeritud mikrogliia rakkudes. Antud töö eesmärgiks oli uurida kuidas CX3CR1(GFP/+) hiirte mikrogliiarakkude molekulaarne muster on mõjutatud LPS manustamise poolt.