Nitro-oleic acid regulates growth factor-induced differentiation of bone marrow-derived macrophages

Abstract

Many diseases accompanied by chronic inflammation are connected with dysregulated activation of macrophage subpopulations. Recently, we reported that nitro-fatty acids (NO2-FAs), products of metabolic and inflammatory reactions of nitric oxide and nitrite, modulate macrophage and other immune cell functions. Bone marrow cell suspensions were isolated from mice and supplemented with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with NO2-OA for different times. RAW 264.7 macrophages were used for short-term (1–5 min) experiments. We discovered that NO2-OA reduces cell numbers, cell colony formation, and proliferation of macrophages differentiated with colony-stimulating factors (CSFs), all in the absence of toxicity. In a case of GM-CSF-induced bone marrow-derived macrophages (BMMs), NO2-OA acts via downregulation of signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK) activation. In the case of M-CSF-induced BMMs, NO2-OA decreases activation of M-CSFR and activation of related PI3K and ERK. Additionally, NO2-OA also attenuates activation of BMMs. In aggregate, we demonstrate that NO2-OA regulates the process of macrophage differentiation and that NO2-FAs represent a promising therapeutic tool in the treatment of inflammatory pathologies linked with increased accumulation of macrophages in inflamed tissues.

Nitroalkene fatty acids modulate bile acid metabolism and lung function in obese asthma

“…CXA-10 (P.O., daily, 2 wk) activated multiple tissue defense mechanisms and inhibited pro-inflammatory signaling responses. These basic research and clinical studies have produced reproducible data that has culminated into a profile of targets in various disease pathologies that include a) the inhibition of NF-kB-regulated inflammatory cytokine, adipokine (leptin and adiponectin) and adhesion molecule expression 20 , 33 , 34 , b) the inhibition of pro-inflammatory macrophage activation 35 , 36 , c) the activation of Nrf2-regulated adaptive gene expression 37 , 38 and d) the prevention and reversal of fibrosis 19 , 36 , 39 , 40 . Based on this data, a clinical trial administering CXA-10 for 6 weeks is ongoing in obesity-associated asthma (NCT03762395).…”

Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors

“…Also, some actions on neutrophils have been described; nitro-oleic acid induced apoptosis of neutrophils and their phagocytosis by alveolar macrophages in a model of allergic airway disease (Reddy et al, 2013 ) and reduced neutrophil infiltration in a murine model of myocardial ischemia and reperfusion (Rudolph et al, 2010 ). Nitro-oleic acid reduced the activation of signaling pathways, such as STAT5, ERK, and PI3K, and the expression of adhesion molecules and pro-inflammatory cytokines in RAW 264.7 macrophages or mice bone marrow-derived macrophages (Rudolph et al, 2010 ; Ambrozova et al, 2016 ; Verescakova et al, 2017 ). Furthermore, nitro-oleic acid (5 μM) increased the expression of CD36 in RAW 264.7 macrophages, and ligand binding analysis showed the interaction of nitro-oleic acid with CD36 (Vazquez et al, 2020 ).…”

Fatty acid nitroalkene reversal of established lung fibrosis

“…These pro-inflammatory signaling actions induce the expression of α-SMA in vimentin positive FB [ 135 ], with the combination of these two markers serving as an index of myoFB quantity and differentiation state [ 136 ]. NFκB signaling, inhibited by NO 2 -OA binding to critical p50 and p65 subunit cysteines, limits pro-inflammatory mediator expression in multiple cell systems [ 26 , 32 , 72 , 94 , 95 , 121 , 137 , 138 ]. Numbers of myoFB were decreased by NO 2 -OA in PCLS from both control and bleomycin-treated mice, with the population of vimentin positive cells not altered ( Fig.…”