{"doi":"10.3389/fimmu.2020.00201","title":"Key Components of the Complement Lectin Pathway Are Not Only Required for the Development of Inflammatory Arthritis but Also Regulate the Transcription of Factor D","abstract":"The complement system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Besides driving lectin pathway (LP) activation, the mannan-binding lectin (MBL)-associated serine proteases (MASPs) also play a key role in regulating the alternative pathway (AP). We evaluated the effects of N-acetylgalactosamine (GalNAc)-conjugated MASP-1 and MASP-2 duplexes in vitro and in mice with and without arthritis to examine whether knockdown of MASP-1 and MASP-2 expression affects the development of arthritis. GalNAc-siRNAs for MASP-1 and MASP-2 demonstrated robust silencing of MASP-1 or MASP-2 at pM concentrations in vitro. To evaluate the impact of silencing in arthritic mice, we used the collagen antibody-induced arthritis (CAIA) mouse model of RA. Mice were injected a 10 mg/kg dose of GalNAc-siRNAs 3x s.q. prior to the induction of CAIA. Liver gene expression was examined using qRT-PCR, and protein levels were confirmed in the circulation by sandwich immunoassays and Western blot. At day 10, CAIA mice separately treated with MASP-1 and MASP-2 duplexes had a specific reduction in expression of liver MASP-1 (70-95%, p < 0.05) and MASP-2 (90%, p < 0.05) mRNA, respectively. MASP-1-siRNA treatment resulted in a 95% reduction in levels of MASP-1 protein in circulation with no effect on MASP-2 levels and clinical disease activity (CDA). In mice injected with MASP-2 duplex, there was a significant (p < 0.05) 90% decrease in ex vivo C4b deposition on mannan, with nearly complete elimination of MASP-2 in the circulation. MASP-2 silencing initially significantly decreased CDA by 60% but subsequently changed to a 40% decrease vs. control. Unexpectedly, GalNAc-siRNA-mediated knockdown of MASP-1 and MASP-2 revealed a marked effect of these proteins on the transcription of FD under normal physiological conditions, whereas LPS-induced inflammatory conditions reversed this effect on FD levels. LPS is recognized by Toll-like receptor 4 (TLR4), we found MBL not only binds to TLR4 an interaction with a Kd of 907 nM but also upregulated FD expression in differentiated adipocytes. We show that MASP-2 knockdown impairs the development of RA and that the interrelationship between proteins of the LP and the AP may extend to the transcriptional modulation of the FD gene.","journal":"Frontiers in Immunology","year":2020,"id":81782,"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":0.9639,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":423307,"name":"Anna Borodovsky","orcid":null,"position":1,"is_corresponding":false},{"id":124041,"name":"Robert I Scheinman","orcid":"0000-0001-8485-6620","position":2,"is_corresponding":false},{"id":423308,"name":"Nhu Ho","orcid":null,"position":3,"is_corresponding":false},{"id":423309,"name":"Joseline Ramos Ramirez","orcid":null,"position":4,"is_corresponding":false},{"id":422462,"name":"József Dobó","orcid":"0000-0001-9187-8502","position":5,"is_corresponding":false},{"id":251673,"name":"Péter Gál","orcid":"0000-0001-8987-2080","position":6,"is_corresponding":false},{"id":422463,"name":"Jared Lindenberger","orcid":"0000-0003-2044-6715","position":7,"is_corresponding":false},{"id":423310,"name":"Annette G. Hansen","orcid":null,"position":8,"is_corresponding":false},{"id":422464,"name":"Dhruv Desai","orcid":"0000-0003-0864-396X","position":9,"is_corresponding":false},{"id":422465,"name":"Rasmus Pihl","orcid":"0000-0003-1409-4135","position":10,"is_corresponding":false},{"id":422466,"name":"Steffen Thiel","orcid":"0000-0002-4817-155X","position":11,"is_corresponding":false},{"id":124037,"name":"Nirmal K Banda","orcid":"0000-0002-5291-5136","position":12,"is_corresponding":false},{"id":41942,"name":"V. Michael Holers","orcid":"0000-0002-5634-7746","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-18T21:52:58.921847Z","pmid":"32153567","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":[]}