The role of pannexin hemichannels in inflammation and regeneration

Abstract

Tissue injury involves coordinated systemic responses including inflammatory response, targeted cell migration, cell-cell communication, stem cell activation and proliferation, and tissue inflammation and regeneration. The inflammatory response is an important prerequisite for regeneration. Multiple studies suggest that extensive cell-cell communication during tissue regeneration is coordinated by purinergic signaling via extracellular adenosine triphosphate (ATP). Most recent data indicates that ATP release for such communication is mediated by hemichannels formed by connexins and pannexins. The Pannexin family consists of three vertebrate proteins (Panx 1, 2, and 3) that have low sequence homology with other gap junction proteins and were shown to form predominantly non-junctional plasma membrane hemichannels. Pannexin-1 (Panx1) channels function as an integral component of the P2X/P2Y purinergic signaling pathway and is arguably the major contributor to pathophysiological ATP release. Panx1 is expressed in many tissues, with highest levels detected in developing brain, retina and skeletal muscles. Panx1 channel expression and activity is reported to increase significantly following injury/inflammation and during regeneration and differentiation. Recent studies also report that pharmacological blockade of the Panx1 channel or genetic ablation of the Panx1 gene cause significant disruption of progenitor cell migration, proliferation, and tissue regeneration. These findings suggest that pannexins play important roles in activation of both post-injury inflammatory response and the subsequent process of tissue regeneration. Due to wide expression in multiple tissues and involvement in diverse signaling pathways, pannexins and connexins are currently being considered as therapeutic targets for traumatic brain or spinal cord injuries, ischemic stroke and cancer. The precise role of pannexins and connexins in the balance between tissue inflammation and regeneration needs to be further understood.

Keywords: FGF; P2X7R; Panx1; connexin; inflammation; pannexin; regeneration; stem cell.

Figure 1

Scheme of inflammation and wound healing in epithelial tissue. (A) The glandular epithelial cells form a selective permeability barrier separating luminal content from underlying tissues. (A) In the epithelial tissue cell damage induces ATP externalization from injured and necrotic cells and later from infiltrating neutrophils, monocytes (macrophages precursors), and macrophages. ATP is released through pannexin hemichannels, specifically through Panx1. ATP activates monocytes, macrophages, and mast cells (also known as effector cells in allergic and inflammatory diseases) that migrate to the site of injury. (B) In addition during an inflammatory response, eosinophils and neutrophils migrate from the bloodstream into tissues. They contribute to the recruitment of monocytes and macrophages. Macrophages and mast cells express P2X7 receptors (P2X7Rs), members of the family of ionotropic ATP-gated receptors. ATP activated P2X7Rs are associated with injury activation of the inflammasome within macrophages and transformation of macrophages into pro-inflammatory M1 type of macrophages. M1 macrophages inhibit cell proliferation and induce inflammation by releasing IL-1 and IL-18 and ATP. They also secrete degradative enzymes, such as matrix metalloproteinases (MMPs), collagenase, and elastase, and are crucial in induction of extracellular matrix (ECM) remodeling and tissue reorganization, allowing them and other cells (including epithelial and epithelial stem/progenitor cells) to migrate through tissues. High concentration of ATP can also act as a Panx1 channel inhibitor and thus Panx1 acts as a regulator of its own function (black looped arrow) (C) Macrophages are very plastic cells that function as control switches of the immune system, providing a balance between pro- and anti-inflammatory responses. Macrophages could be transformed into pro-healing M2 macrophages by signals released from fibroblasts or by other external signals. M2 macrophages express IL-10, growth factors, and tissue inhibitor of metalloproteinases (TIMPs) suppress immune and inflammatory responses and promote cell proliferation and tissue repair, and angiogenesis. Migrating fibroblasts secrete FGFs and other growth factors that support tissue morphogenesis. Stem and progenitor cells also express pannexin hemichannels, which are involved in regulation of progenitor cell migration and differentiation.