TNF-α Induces a Pro-Inflammatory Phenotypic Shift in Monocytes through ACSL1: Relevance to Metabolic Inflammation

• Published in: Cellular physiology and biochemistry Vol. 52; no. 3; pp. 397 - 407
• Main Authors: Al-Rashed, Fatema, Ahmad, Zunair, Iskandar, Mina Amin, Tuomilehto, Jaakko, Al-Mulla, Fahd, Ahmad, Rasheed
• Format: Journal Article
• Language: English
• Published: Germany Cell Physiol Biochem Press GmbH & Co KG 2019
• Subjects: Cell Line; Chemokine CCL2 - analysis; Coenzyme A Ligases - antagonists & inhibitors; Coenzyme A Ligases - genetics; Coenzyme A Ligases - metabolism; Gene Expression Regulation - drug effects; HLA-DR Antigens - genetics; HLA-DR Antigens - metabolism; Humans; Inflammation - metabolism; Inflammation - pathology; Interleukin-1beta - analysis; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; NF-kappa B - metabolism; Phosphorylation; Receptors, IgG - genetics; Receptors, IgG - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Triazenes - chemistry; Triazenes - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Monocytes; Inflammation; TNF-α; ACSL1; CD11c
• ISSN: 1015-8987; 1421-9778
• DOI: 10.33594/000000028

TNF-α-mediated pro-inflammatory phenotypic change in monocytes is known to be implicated in the pathogenesis of metabolic inflammation and insulin resistance. However, the mechanism by which TNF-α-induces inflammatory phenotypic shift in monocytes is poorly understood. Since long-chain acyl-CoA synthetase 1 (ACSL1) is associated with inflammatory monocytes/macrophages, we investigated the role of ACSL1 in the TNF-α-driven inflammatory phenotypic shift in the monocytes.
Monocytes (Human monocytic THP-1 cells) were stimulated with TNF-α. Inflammatory phenotypic markers (CD16, CD11b, CD11c and HLA-DR) expression was determined with real time RTPCR and flow cytometry. IL-1β and MCP-1 were determined by ELISA. Signaling pathways were identified by using ACSL1 inhibitor, ACSL1 siRNA and NF-κB reporter monocytic cells. Phosphorylation of NF-κB was analyzed by western blotting and flow cytometry.
Our data show that TNF-α induced significant increase in the expression of CD16, CD11b, CD11c and HLA-DR. Inhibition of ACSL1 activity in the cells with triacsin C significantly suppressed the expression of these inflammatory markers. Using ACSL-1 siRNA, we further demonstrate that TNF-α-induced inflammatory markers expression in monocytic cells requires ACSL1. In addition, IL-1b and MCP-1 production by TNF-α activated monocytic cells was significantly blocked by the inhibition of ACSL-1 activity. Interestingly, elevated NF-κB activity resulting from TNF-α stimulation was attenuated in ACSL1 deficient cells.
Our findings provide an evidence that TNF-α-associated inflammatory polarization in monocytes is an ACSL1 dependent process, which indicates its central role in TNF-α-driven metabolic inflammation.