Intercellular metabolite communication via Pannexin 1 coordinates inflammation

Medina, Christopher, Microbiology - School of Medicine, University of Virginia
Ravichandran, Kodi, MD-MICR Microbiology, University of Virginia

Throughout the years evolution has shaped and molded the human species. This is highlighted by conserved genes and mechanisms that exist within us, including those involved in protecting our system from pathogen, disease, and insult. At the crux of this protection is inflammation, which is essential for survival. However, while inflammation is required to protect from foreign insults and even sterile injury, proper resolution must also occur. Unchecked inflammatory responses can cause excessive damage to the areas affected, and magnify health complications. Therefore, mechanisms that regulate and dampen inflammation are as important as inflammation itself. Here, in this dissertation, I have focused on how pannexin 1 channels regulate inflammatory responses in two different settings: the process of apoptosis, and the function of T regulatory cells in airway inflammation.
The first part of this dissertation examines how apoptotic cells can remain immunologically silent. I describe one mechanism by which apoptotic cells, with an intact cell membrane, can regulate and orchestrate the specific release of metabolites. Such extracellular metabolites, in turn, are able to signal to the surrounding cells to maintain an anti-inflammatory state within the tissue. Some of these metabolites were quite potent in their signaling capacity and we could combine a few select metabolites and harness their properties for therapeutic potential in several disease models.
In the second part of this dissertation, I describe a novel mechanism by which Teff and Treg cells can communicate via extracellular adenine nucleotides. This occurs to optimally mediate suppression of the immune response by Treg cells to inhibit excessive proliferation of Teff cell during airway inflammation. This crosstalk was dependent on Panx1 channels for ATP release via either Teff or Treg cells and in turn regulated the severity of allergic airway inflammation. Collectively, the data from my dissertation suggest novel mechanisms by which apoptotic cells and Panx1 can mediate intercellular communication between cells which is important for the proper control of inflammation. This has implications for several inflammatory disorders and identifies ways we may be able to harness certain aspects of Panx1 for therapeutic benefit. It also advances the Pannexin field by widening the scope through which we view Panx1, as not just an ATP release channel.

PHD (Doctor of Philosophy)
Pannexin 1, inflammation, metabolite, metabolism, airway, T cell
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