Connexins and their channels in inflammation

Abstract

Inflammation may be caused by a variety of factors and is a hallmark of a plethora of acute and chronic diseases. The purpose of inflammation is to eliminate the initial cell injury trigger, to clear out dead cells from damaged tissue and to initiate tissue regeneration. Despite the wealth of knowledge regarding the involvement of cellular communication in inflammation, studies on the role of connexin-based channels in this process have only begun to emerge in the last few years. In this paper, a state-of-the-art overview of the effects of inflammation on connexin signaling is provided. Vice versa, the involvement of connexins and their channels in inflammation will be discussed by relying on studies that use a variety of experimental tools, such as genetically modified animals, small interfering RNA and connexin-based channel blockers. A better understanding of the importance of connexin signaling in inflammation may open up towards clinical perspectives.

Keywords: Connexins; cytokines; gap junctions; hemichannels; inflammation.

Figure 1. Structure of connexins and their channels.

GJs appear as plaques at the cell plasma membrane surface and are formed by the interaction of 2 HCs of adjacent cells. Each HC is composed of 6 Cx proteins, which are transmembrane proteins consisting of a cytoplasmic loop, 2 extracellular loops, a cytoplasmic C-terminal tail and a cytoplasmic N-terminal tail. (CL, cytoplasmic loop; EL, extracellular loop; TM, transmembrane domain).

Figure 2. Role of connexin signaling in the initiation of inflammation.

PAMPs or DAMPs can interact with Toll-like receptors, which undergo dimerization upon activation. This triggers the migration of NF-κβ to the nucleus, where it activates gene transcription of pro-IL-1β. The latter is cleaved to mature IL-1β by caspase 1 in the cytosol, which influences the production of a number of pro-inflammatory mediators, such as TNF-α, IL-6 and NOS. This characterizes the onset of the inflammatory reaction. GJs can transfer ATP between neighboring cells. HCs can release ATP into the extracellular environment after opening by pathogenic stimuli. ATP can then interact with P2X7 purinergic receptors at the cell plasma membrane and can influence the inflammatory process. (ATP, adenosine triphosphate; DAMPs, damage-associated molecular patterns; IL, interleukin; NF, nuclear factor; NOS, nitric oxide synthase; PAMPS, pathogen-associated molecular patterns; TNF, tumor necrosis factor).