Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-\u03b1

Fatema Al-Rashed,Zunair Ahmad,Fahd Al-Mulla,Lina M Obeid,Reeby Thomas,Rasheed Ahmad,Ashley J Snider,Motasem Melhem,Yusuf A Hannun

doi:10.1038/s41598-020-73912-5

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: 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-1β and MCP-1. In contrast, inhibition of acid SMase (aSMase) activity did not attenuate CD11c expression or secretion of IL-1β 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.

Highlights

Obesity is associated with elevated levels of Tumor necrosis factor-α (TNF-α) and proinflammatory CD11c monocytes/ macrophages
Our data show that DNR induces inflammatory change in monocytes that was comparable to tumor necrosis factor (TNF)-α, manifested by increased CD11c expression (Fig. 1A–C)
Tumor necrosis factor-α (TNF-α), which is overexpressed in obese humans and rodents, plays a central role in metabolic inflammation and insulin resistance

Summary

Introduction

Obesity is associated with elevated levels of TNF-α and proinflammatory CD11c monocytes/ macrophages. Since neutral sphingomyelinase-2 (nSMase[2]: SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether nSMase[2] contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-α. SMPD3 was elevated in PBMCs from obese individuals and positively corelated with TNF-α gene expression These findings indicate that nSMase[2] acts, at least in part, as a master switch in the TNF-α mediated inflammatory responses in monocytes/macrophages. Obesity-driven changes of the adipose tissue monocytes/macrophages alter the secretion of the proinflammatory cytokines which contribute to the progression of inflammation and development of insulin resistance. Inhibition of nSMase[2] attenuated the TNF-α-mediated secretion of inflammatory markers IL-1β and MCP-1. Our data reveal an interesting and novel role of nSMase[2] in TNF-α-driven inflammation

Methods

Results

Conclusion