{"doi":"10.1101/2020.05.06.080382","title":"Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":126596,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":316839,"name":"Zunair Ahmad","orcid":"0000-0002-8677-7413","position":1,"is_corresponding":false},{"id":316840,"name":"Reeby Thomas","orcid":"0000-0001-9933-0285","position":2,"is_corresponding":false},{"id":316841,"name":"Motasem Melhem","orcid":"0000-0003-4236-2467","position":3,"is_corresponding":false},{"id":316842,"name":"Ashley J. Snider","orcid":"0000-0002-1515-4171","position":4,"is_corresponding":false},{"id":316843,"name":"Lina M. Obeid","orcid":"0000-0002-0734-0847","position":5,"is_corresponding":false},{"id":104495,"name":"Fahd Al‐Mulla","orcid":"0000-0001-5409-3829","position":6,"is_corresponding":false},{"id":271166,"name":"Yusuf A. Hannun","orcid":"0000-0003-3349-3369","position":7,"is_corresponding":false},{"id":316844,"name":"Rasheed Ahmad","orcid":"0000-0001-5746-0743","position":8,"is_corresponding":false},{"id":316838,"name":"Fatema Al‐Rashed","orcid":"0000-0002-5825-7701","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}