Furanoid F-Acid F6 Uniquely Induces NETosis Compared to C16 and C18 Fatty Acids in Human Neutrophils

Abstract

Various biomolecules induce neutrophil extracellular trap (NET) formation or NETosis. However, the effect of fatty acids on NETosis has not been clearly established. In this study, we focused on the NETosis-inducing ability of several lipid molecules. We extracted the lipid molecules present in Arabian Gulf catfish (Arius bilineatus, Val) skin gel, which has multiple therapeutic activities. Gas chromatography–mass spectrometry (GC-MS) analysis of the lipid fraction-3 from the gel with NETosis-inducing activity contained fatty acids including a furanoid F-acid (F6; 12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid) and common long-chain fatty acids such as palmitic acid (PA; C16:0), palmitoleic acid (PO; C16:1), stearic acid (SA; C18:0), and oleic acid (OA; C18:1). Using pure molecules, we show that all of these fatty acids induce NETosis to different degrees in a dose-dependent fashion. Notably, F6 induces a unique form of NETosis that is rapid and induces reactive oxygen species (ROS) production by both NADPH oxidase (NOX) and mitochondria. F6 also induces citrullination of histone. By contrast, the common fatty acids (PA, PO, SA, and OA) only induce NOX-dependent NETosis. The activation of the kinases such as ERK (extracellular signal-regulated kinase) and JNK (c-Jun N-terminal kinase) is important for long-chain fatty acid-induced NETosis, whereas, in F-acid-induced NETosis, Akt is additionally needed. Nevertheless, NETosis induced by all of these compounds requires the final chromatin decondensation step of transcriptional firing. These findings are useful for understanding F-acid- and other fatty acid-induced NETosis and to establish the active ingredients with therapeutic potential for regulating diseases involving NET formation.

Oleic acid-based nanosystems for mitigating acute respiratory distress syndrome in mice through neutrophil suppression: how the particulate size affects therapeutic efficiency

“…It is generally recognized that NETosis is a unique type of neutrophil death via the NADPH-oxidase (Nox)-dependent pathway [40]. Previous evidence [41] expressed that OA only induces Nox-dependent NETosis in human neutrophils. This explains the enhanced NET formation and cell death by the nanosystems with an OA dose at 10 μg/ml.…”

Lactobacillus pentosus Increases the Abundance of Akkermansia and Affects the Serum Metabolome to Alleviate DSS-Induced Colitis in a Murine Model

“…The production of certain metabolites indicates that inflammation has occurred. Most commonly, inflammation induces neutrophil aggregation and promotes the formation of neutrophil extracellular traps, and furanoid fatty acids induce NADPH oxidase and the production of reactive oxygen species in the mitochondria (Khan et al, 2018). Chemotaxis neutrophils can also secrete leukotriene B4 substances, which increase the recruitment of neutrophils (Majumdar et al, 2016).…”

The Influence of Dietary Fatty Acids on Immune Responses

“…Other n-6 PUFAs ↓ T cell activation and ↓ IL-2 and IFN-γ production by EPA-DC stimulated T cells (AA) [58] ↓ Responses to LPS, independent from NF-κB and eicosanoid system [58] Neutrophils ↑ TNFR1 and TNFR2 receptor expression mediated via PKC, ERK1/2 and cPLA 2 (AA) [88] ↓ ATP production and ↑ LDH release [89] ↑ Mitochondria depolarization and lipid accumulation [90] ↑ ROS production dependent from calcium signaling (AA) [86] T cells ↓ T-cell proliferation in DCs and T cell co-culture by ↑ FoxP3 + T cell population (AA) [77] OA Neutrophils ↑ ROS production, phagocytosis and killing capacities, ↑ VEGF, CXCL3 and IL-1β production [91][92][93] ↑ NETosis [94] T cells ↑ Apoptosis via caspase-3 pathway (high doses) [87] PA Macrophages ↑ Activation of TLR4 and NF-κB pathway [95] ↑ IL-18 and TNF-α secretion [96] ↑ Activation of TLR2 and NLRP3 inflammasome and ↑ of IL-1β-secretion [97] Dendritic cells ↑ TLR4 endocytosis, ↑ CD86, and CD83 expression and ↑ TLR4-dependent secretion of IL-1β via NF-κB canonical pathway [98] Dendritic cells ↑ ROS production [98] ↑…”

“…Both EPA and DHA increase the generation of ROS and TNF-α, but only DHA can enhance phagocytosis, antifungal properties, and IL-1β secretion by neutrophils [59]. Additionally, Khan et al showed that dietary SFAs and MUFAs can induce NADPH-oxidase-dependent neutrophil extracellular traps formation in human neutrophils in vitro [94]. To explain these contradictory effects of various PUFAs on neutrophil biology, it has been hypothesized that the ratio of n-6/n-3 PUFAs, rather than n-3 PUFAs amounts, is essential to exert anti-inflammatory effects [152].…”