{"doi":"10.1021/acsptsci.2c00098","title":"Carboxylesterase 1d Inactivation Augments Lung Inflammation in Mice","abstract":"Carboxylesterases are members of the serine hydrolase superfamily and metabolize drugs, pesticides, and lipids. Previous research showed that inhibition of carboxylesterase 1 (CES1) in human macrophages altered the immunomodulatory effects of lipid mediators called prostaglandin glyceryl esters, which are produced by cyclooxygenase-catalyzed oxygenation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Ces1d – the mouse ortholog of human CES1 – is the most abundant Ces isoform in murine lung tissues and alveolar macrophages and a major target of organophosphate poisons. Monoacylglycerol lipase (Magl) is also expressed in murine lung and is the main enzyme responsible for 2-AG catabolism. Several metabolic benefits are observed in Ces1d−/− mice fed a high-fat diet; thus, we wondered whether pharmacological and genetic inactivation of Ces1d in vivo might also ameliorate the acute inflammatory response to lipopolysaccharide (LPS). C57BL/6 mice were treated with WWL229 (Ces1d inhibitor) or JZL184 (Magl inhibitor), followed 30 min later by either LPS or saline. Wild-type (WT) and Ces1d−/− mice were also administered LPS to determine the effect of Ces1d knockout. Mice were sacrificed at 6 and 24 h, and cytokines were assessed in serum, lung, liver, and adipose tissues. Lipid mediators were quantified in lung tissues, while activity-based protein profiling and enzyme assays determined the extent of lung serine hydrolase inactivation by the inhibitors. WWL229 was shown to augment LPS-induced lung inflammation in a female-specific manner, as measured by enhanced neutrophil infiltration and Il1b mRNA. The marked Ces inhibition in female lung by 4 h after drug treatment might explain this sex difference, although the degree of Ces inhibition in female and male lungs was similar at 6 h. In addition, induction of lung Il6 mRNA and prostaglandin E2 by LPS was more pronounced in Ces1d−/− mice than in WT mice. Thus, WWL229 inhibited lung Ces1d activity and augmented the female lung innate immune response, an effect observed in part in Ces1d−/− mice and Ces1d/CES1-deficient murine and human macrophages. In contrast, JZL184 attenuated LPS-induced Il1b and Il6 mRNA levels in female lung, suggesting that Ces1d and Magl have opposing effects. Mapping the immunomodulatory molecules/pathways that are regulated by Ces1d in the context of lung inflammation will require further research.","journal":"ACS Pharmacology & Translational Science","year":2022,"id":245721,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":881422,"name":"Abdolsamad Borazjani","orcid":null,"position":1,"is_corresponding":false},{"id":881423,"name":"Hannah L. Scheaffer","orcid":null,"position":2,"is_corresponding":false},{"id":880864,"name":"J. Allen Crow","orcid":"0000-0002-2365-7852","position":3,"is_corresponding":false},{"id":881424,"name":"Ann Marie McBride","orcid":null,"position":4,"is_corresponding":false},{"id":881425,"name":"Oluwabori Adekanye","orcid":null,"position":5,"is_corresponding":false},{"id":881426,"name":"Caitlin B. Wonnacott","orcid":null,"position":6,"is_corresponding":false},{"id":601122,"name":"Richard Lehner","orcid":"0000-0002-6008-1805","position":7,"is_corresponding":false},{"id":337373,"name":"Barbara L.F. Kaplan","orcid":"0000-0002-1992-4145","position":8,"is_corresponding":false},{"id":471235,"name":"Matthew K. Ross","orcid":"0000-0002-9167-8452","position":9,"is_corresponding":false},{"id":881421,"name":"Brittany N. Szafran","orcid":null,"position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T00:23:39.284121Z","pmid":"36268116","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":[]}