Elevated CO2 regulates monocyte differentiation and macrophage activation

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Title: Elevated CO2 regulates monocyte differentiation and macrophage activation
Authors: Strowitzki, Moritz
Permanent link: http://hdl.handle.net/10197/12951
Date: 2022
Online since: 2022-06-30T13:57:47Z
Abstract: Monocyte differentiation and macrophage activation play a central role during initial inflammatory responses and subsequent wound healing processes. Recent studies suggest that elevated CO2 suppresses immune cell activity during inflammation. However, little is known about how monocytes and macrophages sense and adapt upon different CO2 levels. In the present thesis, it was found that elevated CO2 reduced monocyte differentiation and macrophage activation, which subsequently diminished their ability to migrate and promote wound healing in a cell culture model of intestinal epithelial cell injury. Mechanistically, CO2 reduced protein kinase C (PKC) activity in a manner dependent upon decreased extra- and intracellular pH. Elevated CO2 levels resulted in reduction of both extra- and intracellular pH, indicating a coupled pH response in monocytes and macrophages. Pharmacological and genetic inhibition of carbonic anhydrases (CA) uncoupled the CO2-elicited intracellular pH-response, thereby preventing CO2-sensitivity during monocyte differentiation activation, and cell migration. CRISPR technology-driven genetic up-regulation of CA2 enhanced CO2-sensitivity in intestinal epithelial cells, which under untreated conditions only marginally express CA2 and did not respond to increased CO2 levels. Patients with chronic lung diseases and elevated systemic CO2 levels, were at risk developing anastomotic leakage following gastro-intestinal surgery, indicating impaired wound healing in patients with high intraoperative CO2 levels. Furthermore, intraoperative CO2 levels negatively correlated with macrophage infiltration. The negative CO2-associated correlation with macrophage infiltration was not evident in patients with low epithelial CA2 expression. In contrast, the negative CO2-associated correlation with macrophage infiltration was even more pronounced in patients with high mucosal CA2 expression. Taken together, CO2 is immuno-modulatory and sensed in monocytes and macrophages by a CA2-dependent coupled intracellular pH-response.
Type of material: Doctoral Thesis
Publisher: University College Dublin. School of Medicine
Qualification Name: Ph.D.
Copyright (published version): 2022 the Author
Keywords: Monocyte differentiationMacrophage activationCarbon dioxide sensingCarbonic anhydrase
Language: en
Status of Item: Peer reviewed
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by-nc-nd/3.0/ie/
Appears in Collections:Medicine Theses

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