Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS

Abstract

Microglial cells, the resident macrophages of the CNS, exist in a process-bearing, ramified/surveying phenotype under resting conditions. Upon activation by cell damaging factors they get transformed to an amoeboid phenotype releasing various cell products including pro-inflammatory cytokines, chemokines, proteases, reactive oxygen/nitrogen species and the excytotoxic ATP and glutamate. In addition, they engulf pathogenic bacteria or cell debris and phagocytose them. However, already resting/surveying microglia has a number of important physiological functions in the CNS; they e.g. shield small disruptions of the blood-brain barrier by their processes, dynamically interact with synaptic structures and clear surplus synapses during development. In neurodegenerative illnesses they aggravate the original disease by a microglia-based compulsory neuroinflammatory reaction. Therefore, the blockade of this reaction improves the outcome of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. The function of microglia is regulated by a whole array of purinergic receptors classified as P2Y12, P2Y6, P2Y4, P2X4, P2X7, A2A, A3, and being targets for endogenous ATP, ADP, or adenosine. ATP is sequentially degraded by the ecto-nucleotidases and 5’-nucleotidase enzymes to the weak adenosine agonist inosine as an end-product. The appropriate selective agonists/antagonists for purinergic receptors as well as the respective enzyme inhibitors may profoundly interfere with microglial functions and reconstitute the homeostasis of the CNS disturbed by neuroinflammation.

Microglia and Neuroinflammation: What Place for P2RY12?

“…In healthy brain, “resting” microglia exhibit a ramified shape, but in pathological brain, they progressively adopt an amoeboid shape once activated. It is noteworthy that the purinergic receptor density is modified depending on microglial activation state [ 37 ] ( Figure 2 ). Indeed, in response to the chemoattractant or “find-me” signal, ATP, released from damaged cells [ 38 , 39 ], the first step of microglial activation is the stimulation of P2RY12.…”

The Safeguarding Microglia: Central Role for P2Y12 Receptors

“…Purinergic signalling emerges as the key mechanism in the dynamic interactions between neurones and glial cells, with ATP being a classical neurotransmitter and a danger signal damage-associated molecular pattern (DAMP). This duality makes ATP and related purines versatile signalling molecules controlling microglial behaviours in both physiological and pathological context ( Domercq et al, 2013 ; Illes et al, 2020 ).…”

Purinergic Signaling Participates in a Transition Between Functional States of Reactive Microglia and Controls Astrocyte-Driven Neuroinflammation in the Model of Trimethyltin-Induced Neurodegeneration

“…The so-called classical or M1 activation is induced by activation of the classical complement cascade and interferon-γ (IFN-γ), featuring the massive release of pro-in ammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, the induction of nitric oxide synthase-2 (iNOS) and the burst of reactive oxygen species (ROS) [2]. Alternatively, microglia may assume a neuroprotective M2 phenotype, characterized by elevated expression of anti-in ammatory cytokines, such as transforming growth factor β (TGF-β) and IL-10, and the induction of molecular markers, like arginase-1 (Arg1) [3], [4]. The M2 microglial cells clear apoptotic bodies, and re ne synapses through phagocytosis [5] and release protective factors, which may contribute to protection and repair.…”

“…ligand-gated P2X channels and G-protein coupled P2Y receptors, widely expressed at all CNS cell types. ATP promotes microglial chemotaxis towards the challenged area [4], [12] via P2Y 12 receptors [13] and triggers microglial phagocytosis through activation of the P2Y 6 receptor [14].…”

“…Furthermore, ATP promotes the release of pro-in ammatory cytokines IL-1β, TNF-α, and IFN-γ via P2X 7 receptors [15] and induces the astrocytic release of cytokines/chemokines and glia-derived neurotrophic factor (GDNF) via P2Y 1 R [4]. The reach and duration of extracellular ATP actions are tightly regulated by membrane-bound ectonucleotidases, which rapidly hydrolyze ATP, by its sequential hydrolysis to adenosine, as the nal product.…”