{"doi":"10.3389/fmolb.2022.971219","title":"Caspase-1 and the inflammasome promote polycystic kidney disease progression","abstract":"We and others have previously shown that the presence of renal innate immune cells can promote polycystic kidney disease (PKD) progression. In this study, we examined the influence of the inflammasome, a key part of the innate immune system, on PKD. The inflammasome is a system of molecular sensors, receptors, and scaffolds that responds to stimuli like cellular damage or microbes by activating Caspase-1, and generating critical mediators of the inflammatory milieu, including IL-1β and IL-18. We provide evidence that the inflammasome is primed in PKD, as multiple inflammasome sensors were upregulated in cystic kidneys from human ADPKD patients, as well as in kidneys from both orthologous ( PKD1 RC/RC or RC/RC) and non-orthologous ( jck ) mouse models of PKD. Further, we demonstrate that the inflammasome is activated in female RC/RC mice kidneys, and this activation occurs in renal leukocytes, primarily in CD11c+ cells. Knock-out of Casp1 , the gene encoding Caspase-1, in the RC/RC mice significantly restrained cystic disease progression in female mice, implying sex-specific differences in the renal immune environment. RNAseq analysis implicated the promotion of MYC/YAP pathways as a mechanism underlying the pro-cystic effects of the Caspase-1/inflammasome in females. Finally, treatment of RC/RC mice with hydroxychloroquine, a widely used immunomodulatory drug that has been shown to inhibit the inflammasome, protected renal function specifically in females and restrained cyst enlargement in both male and female RC/RC mice. Collectively, these results provide evidence for the first time that the activated Caspase-1/inflammasome promotes cyst expansion and disease progression in PKD, particularly in females. Moreover, the data suggest that this innate immune pathway may be a relevant target for therapy in PKD.","journal":"Frontiers in Molecular Biosciences","year":2022,"id":271286,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"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":393601,"name":"Christopher J. Ward","orcid":"0000-0002-2507-9398","position":1,"is_corresponding":false},{"id":936677,"name":"Micaila E. Lopez","orcid":null,"position":2,"is_corresponding":false},{"id":936678,"name":"Shaneann Fross","orcid":null,"position":3,"is_corresponding":false},{"id":936185,"name":"Anna L. Heimes Dillon","orcid":"0000-0002-4931-0662","position":4,"is_corresponding":false},{"id":936679,"name":"James D. Meisenheimer","orcid":null,"position":5,"is_corresponding":false},{"id":936680,"name":"Adib J. Rabbani","orcid":null,"position":6,"is_corresponding":false},{"id":936681,"name":"Emily Wedlock","orcid":null,"position":7,"is_corresponding":false},{"id":495576,"name":"Malay Kumar Basu","orcid":"0000-0002-8008-4042","position":8,"is_corresponding":false},{"id":908101,"name":"Kyle Jansson","orcid":"0000-0002-8209-2943","position":9,"is_corresponding":false},{"id":275288,"name":"Peter Rowe","orcid":"0000-0001-9809-3660","position":10,"is_corresponding":false},{"id":363544,"name":"Jason R. Stubbs","orcid":"0000-0003-4580-5745","position":11,"is_corresponding":false},{"id":299686,"name":"Darren P. Wallace","orcid":"0000-0003-4616-7669","position":12,"is_corresponding":false},{"id":782572,"name":"Michael P. Vitek","orcid":"0000-0001-8140-8048","position":13,"is_corresponding":false},{"id":275289,"name":"Timothy A. Fields","orcid":"0000-0003-0665-370X","position":14,"is_corresponding":false},{"id":402675,"name":"Katherine I. Swenson-Fields","orcid":"0000-0002-6097-7847","position":0,"is_corresponding":true}],"reference_count":105,"raw_metadata":null,"created_at":"2026-07-19T00:27:35.206187Z","pmid":"36523654","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":[]}