The role of pannexin1 in the induction and resolution of inflammation

Abstract

Extracellular ATP is an important signaling molecule throughout the inflammatory cascade, serving as a danger signal that causes activation of the inflammasome, enhancement of immune cell infiltration, and fine-tuning of several signaling cascades including those important for the resolution of inflammation. Recent studies demonstrated that ATP can be released from cells in a controlled manner through pannexin (Panx) channels. Panx1-mediated ATP release is involved in inflammasome activation and neutrophil/macrophage chemotaxis, activation of T cells, and a role for Panx1 in inducing and propagating inflammation has been demonstrated in various organs, including lung and the central and peripheral nervous system. The recognition and clearance of dying cells and debris from focal points of inflammation is critical in the resolution of inflammation, and Panx1-mediated ATP release from dying cells has been shown to recruit phagocytes. Moreover, extracellular ATP can be broken down by ectonucleotidases into ADP, AMP, and adenosine, which is critical in the resolution of inflammation. Together, Panx1, ATP, purinergic receptors, and ectonucleotidases contribute to important feedback loops during the inflammatory response, and thus represent promising candidates for new therapies.

Keywords: Extracellular ATP; Inflammation; Pannexin 1; Resolution.

Figure. Roles of Panx1 during the different phases of the inflammatory response

During the initiation phase of inflammation, ATP released by Panx1 is a danger signal, which activates the inflammasome through signaling to purinergic P2X receptors, resulting in cytokine production. Panx1 channel function also directs immune cell chemotaxis through various purinergic receptors. Irreversible activation of Panx1 results in cell death, especially in neurons. During adaptive immunity, Panx1-dependent ATP release mediates a feedback loop on T cells. Extracellular ATP is known to activate dendritic cells, but the involvement of Panx1 remains to be determined. Clearance of apoptotic cells is crucial for the resolution of inflammation, and Panx1-dependent nucleotide release is involved in this process. Breakdown products of ATP such as adenosine are well-known mediators of anti-inflammation and resolution, and controlled release of ATP by Panx1 may increase adenosine levels through the action of ectonucleotidases.