The Role of Connexin 43 and Pannexin 1 During Acute Inflammation

Abstract

During acute inflammation, the recruitment of leukocytes from the blood stream into the inflamed tissue is a well-described mechanism encompassing the interaction of endothelial cells with leukocytes allowing leukocytes to reach the site of tissue injury or infection where they can fulfill their function such as phagocytosis. This process requires a fine-tuned regulation of a plethora of signaling cascades, which are still incompletely understood. Here, connexin 43 (Cx43) and pannexin 1 (Panx1) are known to be pivotal for the correct communication of endothelial cells with leukocytes. Pharmacological as well as genetic approaches provide evidence that endothelial Cx43-hemichannels and Panx1-channels release signaling molecules including ATP and thereby regulate vessel function and permeability as well as the recruitment of leukocytes during acute inflammation. Furthermore, Cx43 hemichannels and Panx1-channels in leukocytes release signaling molecules and can mediate the activation and function of leukocytes in an autocrine manner. The focus of the present review is to summarize the current knowledge of the role of Cx43 and Panx1 in endothelial cells and leukocytes in the vasculature during acute inflammation and to discuss relevant molecular mechanisms regulating Cx43 and Panx1 function.

Glial Purinergic Signaling in Neurodegeneration

“…Apart from purinergic receptors, several studies have highlighted elevated astrocytic CX43 in neurodegenerative diseases, leading to increased ATP release. Together with other nucleotide transporter such as pannexin-1, they could be targets of choice in order to decrease ATP release and aberrant purinergic signaling in neurodegeneration (203).…”

Effects of Drugs Formerly Proposed for COVID-19 Treatment on Connexin43 Hemichannels

“…Using an in vivo model for acute lung injury, namely lipopolysaccharide-instilled mice, it was shown that Cx43 hemichannels contribute to neutrophil transmigration towards the airspace [56]. Collectively, this could suggest a role for Cx43 hemichannels in neutrophil activation and transmigration in COVID-19 pathogenesis [3,7,21,22,57]. Furthermore, platelet aggregation and thrombosis, which occurs in the prothrombic phase and final phase of COVID-19, can develop towards multi-organ failure with death as outcome [12].…”

“…They seem to become preferentially activated by pathological stimuli, such as decreased extracellular calcium concentrations, mechanical stimulation, oxidative stress, ischemia/reperfusion injuries, and inflammatory conditions [3][4][5]. Among the messengers permeating connexin hemichannels, adenosine triphosphate (ATP) plays a key role in the induction and exacerbation of inflammation [6][7][8][9]. In this respect, inflammation is one of the hallmarks of the coronavirus disease 2019 .…”

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

“…Rosiglitazone also inhibited oxyhemoglobin-induced TLR4 activation and cytokine release in cultured vascular smooth muscle cells through the activation of PPAR-γ [ 42 ]. Moreover, pannexin-1 channels, a transmembrane protein of gap junction channels, regulate vessel function and permeability through releasing of signaling molecules, such as ATP, and contribute to both the innate and acquired immune systems via the modulation of cytokine values [ 240 , 241 ]. Pannexin-1 channels protein gene knockdown remarkably suppress the TLR2/4/NF-kB pathway and promoted cognitive functions in an experimental model of SAH [ 242 ].…”