Abstract
Neuroinflammation is a major component of central nervous system (CNS) injuries and neurological diseases, including Alzheimer’s disease, multiple sclerosis, neuropathic pain, and brain trauma. The activation of innate immune cells at the damage site causes the release of pro-inflammatory cytokines and chemokines, which alter the functionality of nearby tissues and might mediate the recruitment of leukocytes to the injury site. If this process persists or is exacerbated, it prevents the adequate resolution of the inflammation, and ultimately enhances secondary damage. Adenosine 5′ triphosphate (ATP) is among the molecules released that trigger an inflammatory response, and it serves as a chemotactic and endogenous danger signal. Extracellular ATP activates multiple purinergic receptors (P2X and P2Y) that have been shown to promote neuroinflammation in a variety of CNS diseases. Recent studies have shown that Pannexin-1 (Panx1) channels are the principal conduits of ATP release from dying cells and innate immune cells in the brain. Herein, we review the emerging evidence that directly implicates Panx-1 channels in the neuroinflammatory response in the CNS.
Highlights
Over the past few decades, rapid advancements in medical research have led to increasing life expectancy, but the socioeconomic impact of diseases associated with aging, including neurodegenerative diseases, traumatic brain injury (TBI), and stroke, is increasing considerably [1,2,3]
While astrocytic Panx1 channels are less understood in the context of neuroinflammation, they have been shown to be important in the generation and spread of the calcium wave, which is used by astrocytes as mean of intercellular communication [59,60]
In many central nervous system (CNS) injuries, including spinal cord injury, TBI, and brain ischemia, extracellular adenosine triphosphate (ATP) acts as a main danger signal to induce an orchestrated inflammatory response, which may lead to exacerbation of the injury [24,104,148]
Summary
Over the past few decades, rapid advancements in medical research have led to increasing life expectancy, but the socioeconomic impact of diseases associated with aging, including neurodegenerative diseases, traumatic brain injury (TBI), and stroke, is increasing considerably [1,2,3]. Once at the site of injury, microglia begins to resolve the inflammation, mainly by the phagocytosis of cellular debris and dead cells [40] These processes are facilitated by purinergic signaling, mainly by P2Y6-mediated detection of UDP released from dying cells [41]. To reactive astrocytes, activated microglia secrete numerous pro- and anti-inflammatory cytokines (i.e., TNF-α, IL-1β, IL-6, and TGF-β), as well as chemokines (CCL2, CCL3, CCL4, CXCL1, and CXCL4), which promotes infiltration of peripheral leukocytes into the brain. Reactive astrocytes are associated with several brain pathologies, including Alzheimer’s disease, brain ischemia, multiple sclerosis, and neuropathic pain [55,56,57] Among those channels that permit extracellular ATP release in astrocytes, connexin-43 (Cx43) hemichannels are probably the most studied. While astrocytic Panx channels are less understood in the context of neuroinflammation, they have been shown to be important in the generation and spread of the calcium wave, which is used by astrocytes as mean of intercellular communication [59,60]
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