Pharmacological interventions targeting nuclear factor-kappa B signaling in multiple sclerosis

摘要

Multiplesclerosis (MS) isan inflammatory neurodegenerative disease ofthecentral nervous system(CNS). Pathologicalcharacteristics ofthe diseaseincludeactivation ofCNS-intrinsicimmunecells, such as microgliaand astrocytes,and loss of neuronalconnections, myelin and bloodbrain barrier (BBB) integrity as wellas peripheralimmunecellinfiltration into the brain. MS has long been considered a predominantly immunological disease, which has led to the development ofessentially only immune-directed medications. Within this traditional“outside-in”MS hypothesis,a dysregulation ofthe peripheralimmunesystemcauses immunecellinfiltration into the CNS, leading to autoreactivity againstmyelin sheath componentsand secondaryBBBdysfunction. However, recent findings indicatethat overactivation ofmicrogliaand astrocytes represents an important firststep inMS pathology,asappears to bethecasefor other neurodegenerative diseases such as Alzheimer’s disease(AD)and Parkinson’s disease(PD). Within this newhypothesis ofCNS-intrinsic neuroinflammation inMS – also known as the“inside-out”model(Tituset al., 2020), thetranscription factor nuclear factor-kappa B(NFκB) playsacentralrolein the brain. InCNS cells, various triggers, such as bacterial and viralinfections, oxidativestressand othercellular stressors like proteinmisfolding and DNAdamage, lead to NFκBactivation inCNS-immune cellsand subsequent production of pro-inflammatory cytokinesand adhesionmolecules,activation oftheinflammasomecomplex,apoptosisand cellcyclearrest. The production of pro-inflammatorymoleculescausesa microenvironment which provokes CNS-cell degeneration,and is detrimentalfor (re)myelination by oligodendrocytesand neuronalregeneration. Neuroinflammatory cascades in the CNS also preventmicroglia and astrocytes fromexerting their regenerativeeffects on oligodendrocytesand neurons. In addition, microgliaand astrocytes reinforceeach other’s negativeeffects viacytokine-mediated feedback mechanisms, which createa negativeloop that furtheraffects theenvironment for CNScellregeneration. Targeting the NFκBpathwaymay beespecially attractivefor thetreatment ofMS as this transcription factor isalso involved in regulating inflammatory processes within both theinnateand theadaptive peripheralimmunesystems.