Long-Chain Acyl-CoA Synthetase 1 Role in Sepsis and Immunity: Perspectives From a Parallel Review of Public Transcriptome Datasets and of the Literature

Abstract

A potential role for the long-chain acyl-CoA synthetase family member 1 (ACSL1) in the immunobiology of sepsis was explored during a hands-on training workshop. Participants first assessed the robustness of the potential gap in biomedical knowledge identified via an initial screen of public transcriptome data and of the literature associated with ACSL1. Increase in ACSL1 transcript abundance during sepsis was confirmed in several independent datasets. Querying the ACSL1 literature also confirmed the absence of reports associating ACSL1 with sepsis. Inferences drawn from both the literature (via indirect associations) and public transcriptome data (via correlation) point to the likely participation of ACSL1 and ACSL4, another family member, in inflammasome activation in neutrophils during sepsis. Furthermore, available clinical data indicate that levels of ACSL1 and ACSL4 induction was significantly higher in fatal cases of sepsis. This denotes potential translational relevance and is consistent with involvement in pathways driving potentially deleterious systemic inflammation. Finally, while ACSL1 expression was induced in blood in vitro by a wide range of pathogen-derived factors as well as TNF, induction of ACSL4 appeared restricted to flagellated bacteria and pathogen-derived TLR5 agonists and IFNG. Taken together, this joint review of public literature and omics data records points to two members of the acyl-CoA synthetase family potentially playing a role in inflammasome activation in neutrophils. Translational relevance of these observations in the context of sepsis and other inflammatory conditions remain to be investigated.

Transcriptional regulation of ACSL1 by CHREBP and NF-kappa B in macrophages during hyperglycemia and inflammation

“…We show that Acsl1 expression is regulated by CHREBP in hyperglycemia and through NF-kappa B under inflammatory conditions. This is consistent with recent reports showing increased ACSL1 mRNA in peripheral blood from septic patients [25], and also elevation in blood of patients with acute myocardial infarction compared to controls [11], which may reflect an inflammatory response from necrotic tissue as a result of ischemia.…”

A modular framework for the development of targeted Covid-19 blood transcript profiling panels

“…Expression of transcripts comprising this aggregate is generally restricted to neutrophils and robustly increased during sepsis (e.g. as we have described in detail earlier for ACSL1, another transcript belonging to this aggregate [23]). (5) GZMB in A2/S1 (Cytotoxic cells) encodes Granzyme B, a serine protease known to play a role in immune-mediated cytotoxicity.…”

Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation

“…Thus, ACSL/CPT1 may be a critical checkpoint enabling higher rates of oxylipin metabolism during infection. Indeed, a critical role for ACSL1 in sepsis outcome has been proposed [62]. Two other long chain metabolizing ACSLs (3,4) were induced in human sepsis, indicating multiple complex mechanisms of isoform regulation.…”