Date of Award
Summer 8-16-2024
Level of Access Assigned by Author
Open-Access Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biochemistry
Advisor
Julie A. Gosse
Second Committee Member
Melissa Maginnis
Third Committee Member
Juyoung K. Shim
Additional Committee Members
Joshua B. Kelley
Robert E. Gundersen
Abstract
Cetylpyridinium chloride (CPC), a quaternary ammonium antimicrobial, has been used widely in consumer products and agricultural processes at concentrations at high concentrations, thus likely exposing much of the U.S. populace to significant levels of CPC. However, minimal information exists on the eukaryotic toxicology of CPC; hence, information is urgently needed. Mast cells, ubiquitous throughout the human body, particularly at interfaces, are implicated in many diseases and key players in normal immune and nervous system functioning. We have demonstrated that CPC potently (low-μM) inhibits antigen-stimulated function of rat and human mast cells, specifically degranulation, the release of bioactive and inflammatory mediators such as serotonin and histamine, independent of the receptor complex crosslinker used. We have interrogated the underlying biochemical and molecular mechanisms of CPC's inhibition of degranulation. Due to the quaternary nitrogen in its pyridinium headgroup, CPC inhibits degranulation via electrostatic interference. CPC inhibits early tyrosine phosphorylation events, particularly Syk kinase and LAT; the inhibition of Syk and LAT results in reduced Ca2+ efflux from the endoplasmic reticulum. CPC suppression of antigen-stimulated Ca2+ efflux from the endoplasmic reticulum dampens both mitochondrial Ca2+ uptake and store-operated Ca2+ entry (SOCE) into the cytosol, a core mediator of the degranulation pathway. Plasma membrane potential and cytosolic pH, contributors to SOCE, are not affected by CPC. Dampened cytosolic Ca2+ leads to indirect (via SOCE) CPC inhibition of microtubule polymerization, which is necessary for degranulation. This work outlines biochemical mechanisms underlying the effects of CPC on mast cell signaling and allows the prediction of CPC effects on disparate cell types that share similar signaling elements
Recommended Citation
Obeng, Bright, "Antimicrobial Cetylpyridinium Chloride Ironically Inhibits Immune Mast Cell Function: Deciphering Underlying Biochemical Mechanisms" (2024). Electronic Theses and Dissertations. 4070.
https://digitalcommons.library.umaine.edu/etd/4070