{"doi":"10.1101/2024.08.01.606069","title":"Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in Systemic Lupus Erythematosus","abstract":"Abstract Objective We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in vivo regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro coculture model using human PBMCs. Method We first induced lupus-like disease in T cell specific Rictor , a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti- Rictor antisense oligonucleotide ( Rictor -ASO) in a mouse model of lupus: MRL/ lpr mice. Finally, we examined the beneficial effects of RICTOR -ASO on SLE patients’ PBMCs using an in vitro T-B cell coculture assay. Results T cell specific Rictor deficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4 + T cells accompanied by restored CD4 + T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation. In vivo Rictor -ASO treatment improves renal function and pathology in MRL/ lpr mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay, RICTOR- ASO significantly reduce immunoglobulin and autoantibodies production (P < 0.05). Conclusion Targeting mTORC2 could be a promising therapeutic for SLE.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":501800,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9673,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":514460,"name":"Xian Zhou","orcid":"0000-0001-8766-8158","position":1,"is_corresponding":false},{"id":970469,"name":"Michele Carrer","orcid":"0000-0002-6464-9584","position":2,"is_corresponding":false},{"id":262353,"name":"Paymaan Jafar‐Nejad","orcid":"0000-0001-5176-739X","position":3,"is_corresponding":false},{"id":580633,"name":"Yanfeng Li","orcid":"0000-0003-3446-4252","position":4,"is_corresponding":false},{"id":825853,"name":"Naomi M. Gades","orcid":"0000-0003-2581-2243","position":5,"is_corresponding":false},{"id":290231,"name":"Mariam P. Alexander","orcid":null,"position":6,"is_corresponding":false},{"id":1351421,"name":"Mario A. Bautista","orcid":null,"position":7,"is_corresponding":false},{"id":1069184,"name":"Ali A. Duarte Garcia","orcid":null,"position":8,"is_corresponding":false},{"id":287643,"name":"Hu Zeng","orcid":"0000-0002-9909-7732","position":9,"is_corresponding":false},{"id":1323102,"name":"Minji Ai","orcid":"0000-0002-0614-5265","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:10:15.999370Z","pmid":"39131369","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":[]}