Modulation of innate and adaptive immunity by P2X ion channels

• Published in: Current opinion in immunology 2018-06, Vol.52, p.51-59
• Main Authors: Di Virgilio, Francesco, Sarti, Alba Clara, Grassi, Fabio
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animals; Disease Susceptibility; Humans; Immune System - cytology; Immune System - immunology; Immune System - metabolism; Immunity, Innate; Immunomodulation; Ion Channels - genetics; Ion Channels - metabolism; Myeloid Cells - immunology; Myeloid Cells - metabolism; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - metabolism; Signal Transduction; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0952-7915; 1879-0372
• DOI: 10.1016/j.coi.2018.03.026

Sterile or septic inflammation cause ATP accumulation in the extracellular space. ATP activates multiple defensive responses acting at P2X receptors (mainly the P2X7 subtype) expressed by myeloid and lymphoid cells. Activated myeloid and lymphoid cells release in turn ATP which sets in motion an amplification loop (ATP-induced ATP release) that propagates inflammation.▪ •All immune cells express plasma membrane ion channels of the P2X subfamily.•P2X channels are gated by ATP present in the inflammatory microenvironment.•The P2X7 subtype is a potent trigger of inflammatory factor release from phagocytes.•In T lymphocytes the P2X7 receptor supports growth and differentiated functions.•Preclinical data show that P2X7 receptor-targeting inhibits chronic inflammation. Extracellular ATP is a major component of the inflammatory microenvironment where it accumulates following cell and tissue injury but also as a consequence of non-lytic release from activated inflammatory cells. In the inflammatory microenvironment ATP binds and activates nucleotide receptors of the P2Y and P2X subfamilies expressed by immune cells. P2Y receptors are G-protein-coupled, while P2X receptors are cation-selective channels. Changes in the intracellular ion homeostasis triggered by P2X receptor stimulation trigger multiple key responses crucial for initiation, propagation, and resolution of inflammation. In the P2X receptor family, the P2X7 subtype has an important role in the activation of lymphocyte, granulocyte, macrophage and dendritic cell responses. Although clinical studies have been so far rather inconclusive, it is believed that P2X7 receptor targeting might offer novel perspectives for anti-inflammatory therapy.