Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α

Abstract

Obesity is associated with elevated levels of TNF-α and proinflammatory CD11c monocytes /macrophages. TNF-α mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since neutral sphingomyelinase 2 (nSMase2; product of the sphingomyelin phosphodiesterase 3 gene, SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether nSMase2 contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-α. In this study, we demonstrate that the disruption of nSMase activity in monocytes/macrophages either by chemical inhibitor GW4869 or small interfering RNA (siRNA) against SMPD3 results in defects in the TNF-α mediated expression of CD11c. Furthermore, blockage of nSMase in monocytes/macrophages inhibited the secretion of inflammatory mediators IL-1b and MCP-1. In contrast, inhibition of acid SMase (aSMase) activity did not attenuate CD11c expression or secretion of IL-1b and MCP-1. TNF-α-induced phosphorylation of JNK, p38 and NF-κB was also attenuated by the inhibition of nSMase2. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of nSMase2. SMPD3 was elevated in PBMCs from obese individuals and positively corelated with TNF-α gene expression. These findings indicate that nSMase2 acts, at least in part, as a master switch in the TNF-α mediated inflammatory responses in monocytes/macrophages.

Sphingolipid metabolism during Toll‐like receptor 4 (TLR4)‐mediated macrophage activation

“…This made them attractive drug targets exemplified by the anti‐inflammatory effects of sphingomyelin synthase 2 inhibition. Although the inhibition of sphingomyelin synthesis has been shown to reduce TLR4 signalling, targeting neutral sphingomyelinases catalysing the conversion of sphingomyelin to ceramide equally shows a reduced pro‐inflammatory phenotype in macrophages (Al‐Rashed et al, 2020; Amtmann et al, 2003) with a beneficial effect in sepsis (Anderson et al, 2012; Essandoh et al, 2015). This suggests that targeting both sphingomyelin production and conversion to ceramide can exert anti‐inflammatory effects in macrophages, possibly through distinct mechanisms that remain to be identified.…”

Metabolite, Protein, And Tissue Dysfunction Associated With COVID-19 Disease Severity

“…Sphingomyelin is cleaved by sphingomyelinases to produce ceramide which induces a signaling cascade that can lead to the differentiation, proliferation, apoptosis, or cytokine secretion by select immune cell populations. It was recently shown that neutral sphingomyelinase 2 can cause monocyte migration and secretion of inflammatory cytokines in response to soluble TNF-α 142 . Elevated TNF-α has been associated with both obesity and severe cases of COVID-19 143 .…”

Ceramide Metabolism in Cardiovascular Disease: A Network With High Therapeutic Potential

“…29 NSM-2 was, furthermore, shown to be involved in endothelial activation and monocyte recruitment as well as monocyte activation. 30,31 Interestingly, NSM-2 is also involved in the biogenesis of extracellular vesicles, 32 which are important mediators of endothelial-cell function and atherosclerotic plaque development. 33,34 In the context of extracellular vesicles, our group showed that hyperglycemia-induced activation of NSM-2 promotes endothelial apoptosis through the intercellular transfer of ceramides via extracellular vesicles.…”