Background/Purpose: The enzyme acyl-CoA synthetase 1 (ACSL1) converts free fatty acids into their biologically active acyl-CoA derivatives. It is induced by lipopolysaccharide and cytokines (including IFN-gamma and TNF-alpha) and is detected in macrophages in type 1 diabetes mellitus. Increased expression is associated with the inflammatory activation of these cells. ACSL1 promotes membrane phospholipid turnover in activated macrophages, which might contribute to its inflammatory effects. This study was conducted to investigate whether ACSL1 is upregulated in myeloid cells in both human and mouse lupus.

Methods: Acsl1 mRNA levels were measured in human peripheral blood mononuclear cells of patients with lupus and controls, and in splenocytes of TLR7 transgenic mice. Bone marrow-derived macrophages and thioglycollate-elicited peritoneal macrophages from C57/B6 mice were also stimulated with universal type 1 interferon (5, 50 and 500 U/mL), and Acsl1 mRNA and protein levels were measured. Finally, C57/B6 mice were injected i.p. with 0.5 mL of pristane, and blood monocytes and bone marrow monocytes were isolated by negative magnetic bead selection two weeks later. Messenger RNA levels of Acsl1 as well as three lupus interferon signature genes (Isg15, Irf7 and Cxcl10) were determined by  real-time PCR.

Results: ACSL1 mRNA expression was increased in peripheral blood mononuclear cells of patients with lupus (p=0.004) as compared to matched controls. Expression was also increased in splenocytes obtained from the TLR7 transgenic mouse model of lupus (p<0.05). Since Acsl1 expression was increased in both mouse and human lupus, we asked whether Acsl1 could be an interferon-stimulated gene (ISG). We observed that Acsl1 mRNA was induced 3-4 fold by type 1 IFN in thioglycollate-elicited macrophages (p<0.05) and was induced 6-7 fold in bone marrow-derived macrophages (p=0.005), concomitant with an increase in the well-known ISG Cxcl10.  Acsl1 protein was also increased following interferon stimulation. We observed that Acsl1 was induced by pristane in bone marrow monocytes (p=0.03), and was positively associated with the rise of the three lupus interferon signature genes in blood monocytes (p<0.05).  

Conclusion: This is the first demonstration of increased expression of Acsl1 in human lupus as well as in mouse models of this disease. These findings demonstrate that ACSL1 is an ISG. The functional significance of these observations are that type 1 IFN’s may drive expression of Acsl1 in lupus, which in turn, given ACSL1’s ability to promote membrane phospholipid turnover, may modulate the inflammatory potential of monocytes or macrophages in this disease. The direct variation of Acsl1 with the three lupus interferon signature genes we studied further suggests a potential signaling role of ACSL1 and/or its downstream metabolites in either the TLR7 or IFN receptor (IFNAR) signaling pathways in lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/acyl-coa-synthetase-1-expression-is-increased-in-murine-models-of-lupus-as-well-as-in-human-systemic-lupus-erythematosus/