Involvement of Nitric Oxide in Protecting against Radical Species and Autoregulation of M1-Polarized Macrophages through Metabolic Remodeling

Abstract

When the expression of NOS2 in M1-polarized macrophages is induced, huge amounts of nitric oxide (•NO) are produced from arginine and molecular oxygen as the substrates. While anti-microbial action is the primary function of M1 macrophages, excessive activation may result in inflammation being aggravated. The reaction of •NO with superoxide produces peroxynitrite, which is highly toxic to cells. Alternatively, however, this reaction eliminates radial electrons and may occasionally alleviate subsequent radical-mediated damage. Reactions of •NO with lipid radicals terminates the radical chain reaction in lipid peroxidation, which leads to the suppression of ferroptosis. •NO is involved in the metabolic remodeling of M1 macrophages. Enzymes in the tricarboxylic acid (TCA) cycle, notably aconitase 2, as well as respiratory chain enzymes, are preferential targets of •NO derivatives. Ornithine, an alternate compound produced from arginine instead of citrulline and •NO, is recruited to synthesize polyamines. Itaconate, which is produced from the remodeled TCA cycle, and polyamines function as defense systems against overresponses of M1 macrophages in a feedback manner. Herein, we overview the protective aspects of •NO against radical species and the autoregulatory systems that are enabled by metabolic remodeling in M9-polarized macrophages.

Development of a prognostic model based on ferroptosis-related genes for colorectal cancer patients and exploration of the biological functions of NOS2 in vivo and in vitro

“…NOS2 is an inducible isoform of NOS enzymes and functions as a key inflammatory enzyme responsible for nitric oxide biosynthesis ( 33 ). Recent studies connected NOS2 and ferroptosis were almost based on bioinformatic analysis, and NOS2 had been identified as the marker of ferroptosis functions in the process of HIF-1 signaling pathway, NOD-like receptor signaling pathway, central carbon metabolism and macrophage polarization ( 13 , 34 , 35 ). The dysregulation of NOS2 expression can be observed under pathological conditions, including cytokine exposure, inflammation and tumors ( 33 , 36 ).…”

Nitric Oxide as a Determinant of Human Longevity and Health Span

“…Because of its pleiotropic nature, NO can become cytotoxic at high concentrations [70]. The antioxidant effects usually prevail since they are broad and include direct radical scavenging and antioxidant protection against reactive intermediates that induce oxidative stress and damage [71,72]. Excessive concentrations of NO can be generated with high concentrations in the central nervous system and exert detrimental effects, particularly in depression [73].…”