Peter Park

Introduction. Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease of the central nervous system (CNS) characterized by demyelination of CNS axons.¹ Current literature disagrees on the exact immune pathophysiology progression of MS, but evidence shows cells of both the innate and adaptive immune system, specifically microglial cells as one of the most significant contributors.¹ Normally, microglial cells are resident phagocytic cells of the CNS, and one of their primary functions includes phagocytosis of debris in the CNS.² Emerging evidence shows that microglial cells express a G protein-coupled receptor called P2RY12 in the resting state.^2,3 This receptor uniquely distinguishes microglia from other infiltrating monocytes and peripheral macrophages and plays an important role in the biological regulation of homeostasis in microglial cells.^2-4 These findings point to P2RY12 as a previously underappreciated contributor to initial formation of MS lesions. Methods. CNS lesions from the tissue of post-mortem MS patients and mice with experimental autoimmune encephalomyelitis (EAE) model were studied. Different types of white and gray matter lesions were identified, and the homeostatic biomarker P2RY12 was visualized using a 3,3-diaminobenzidine stain and Liquid Permanent Red.⁵ Different cytokines were labeled in postmortem human tissue.⁵ In the EAE mice, P2RY12 was knocked out in female mice, and levels of CNS infiltrating T cell subgroups and were stained for and analyzed.² Results. In human MS tissue, P2RY12 absence increases pro-inflammatory cytokines IL-4 and IFN-y in only active white matter lesions (WMLs) and not in grey matter lesions.⁵ Another study showed that P2RY12 is almost completely absent in initial, early, and active WMLs whereas inactive lesions show no decrease in P2RY12.⁶ P2RY12 knockouts in EAE mice increase Th₁₇ proliferation, differentiation, and worsens the severity of the autoimmune inflammatory response.² Conclusions. Current research focuses on microglial cells as the initial insult to MS by reporting that in the absence of an important homeostatic marker P2RY12, levels of CD4+, Th17, IL-4, and IFN-y are increased.^2,5,6 This suggests that P2RY12 may play an important role in the progression of active MS lesions because its absence signals pro-inflammatory cytokine activity.^2,5,6

1. Sellner J, Rommer PS. Immunological consequences of “immune reconstitution therapy” in multiple sclerosis: A systematic review. Autoimmun Rev. February 2020:102492. doi:10.1016/j.autrev.2020.102492.
2. Zhang J, Li Z, Hu X, et al. Knockout of P2Y12 aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells. Brain Behav Immun. 2017;62:245-255. doi:10.1016/j.bbi.2016.12.001.
3. Poel MVD, Ulas T, Mizee MR, et al. Transcriptional profiling of human microglia reveals grey–white matter heterogeneity and multiple sclerosis-associated changes. Nat Commun. 2019;10(1). doi:10.1038/s41467-019-08976-7.
4. Klein B, Mrowetz H, Barker CM, Lange S, Rivera FJ, Aigner L. Age Influences Microglial Activation After Cuprizone-Induced Demyelination. Front Aging Neurosci. 2018;10. doi:10.3389/fnagi.2018.00278.
5. Wageningen TAV, Vlaar E, Kooij G, Jongenelen CAM, Geurts JJG, Dam A-MV. Regulation of microglial TMEM119 and P2RY12 immunoreactivity in multiple sclerosis white and grey matter lesions is dependent on their inflammatory environment. Acta Neuropathol Commun. 2019;7(1). doi:10.1186/s40478-019-0850-z.
6. Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain. 2017;140(7):1900-1913. doi:10.1093/brain/awx113.