Targeting V-ATPase in human monocytes and macrophages to manipulate inflammation-related mediators

Rao, Zhigang GND

Inflammation is a self-defensive process by the immune system that helps the body to return to homeostasis. Professional innate immune cells with pivotal functions in the immune defense like human monocytes, M1 and M2 macrophages produce abundant levels of mediators including cytokines, pro-inflammatory eicosanoids, as well as specialized proresolving mediators (SPMs). These inflammation-related mediators play indispensable roles in the inflammation process. The vacuolar (H+)-ATPase (V-ATPase) is a universal proton pump that is involved in pH homeostasis, pathogen entry and protein degradation. Although V-ATPase is fundamental in cytokine trafficking and secretion in human monocytes and was implicated in the M2 polarization of murine macrophages, its functional roles in the biosynthesis of inflammation-related lipid mediators in human immune cells like monocytes, M1 and M2 macrophages remained elusive. First, our results indicate that V-ATPase on one hand restricts COX-2 protein levels by limiting p38 MAPK and ERK-1/2 activation, while on the other hand it governs the cellular COX-2 activity through an appropriate intracellular pH. Next, in human M1 macrophages, we show that pharmacologically targeting V-ATPase induces COX-2 protein expression and production of PG and TNF-α levels, thus supporting the anti-tumoral effects of M1 macrophages. Then, we reveal that blockade of V-ATPase during polarization of human M2 macrophages abrogated 15- lipoxygenase-1 (15-LOX-1) expression through MEK-ERK-cMyc signaling pathway and thus prevented the formation of 15-LOX-1-derived SPM precursors and related SPM. Finally, our in vivo data with zymosan-induced peritonitis model propose a critical role of V-ATPase in resolution of inflammation. Together, this thesis provides evidence that V-ATPase differentially regulates the biosynthetic pathways of inflammation-related lipid mediators in human immune cells like monocytes, M1 and M2 macrophages.



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