{"doi":"10.1101/2023.12.23.572573","title":"Neutrophil Extracellular Traps Drive Inflammation in Local Skin and Distant Kidneys in UVB-Irradiated Lupus-Prone Mice","abstract":"ABSTRACT Sunlight is a primary environmental trigger for systemic lupus erythematosus (SLE). However, the mechanisms linking cutaneous inflammation to internal organ damage remain poorly defined. Here, we identify a critical role for neutrophil extracellular trap (NET) formation in a pathogenic skin-kidney axis that drives UVB-induced lupus skin and kidney inflammation. In asymptomatic lupus-prone mice, UVB irradiation elicited concurrent skin and kidney inflammation, characterized by neutrophil infiltration, NET formation, release of NET-associated cytokines and complement C3, and proteinuria. Importantly, targeting nuclear envelope rupture―a critical structural step enabling nuclear chromatin release during NETosis―through Pkcα genetic deletion significantly attenuated NET formation, skin and kidney inflammation, and proteinuria in UVB-irradiated MRL/ lpr;Pkcα -/- mice. Beyond local NETosis, UVB primed skin-infiltrating neutrophils to express the migration receptor CXCR4 alongside proinflammatory cytokines and C3. Using spatiotemporal tracking via photoconversion, we revealed that non-NETting, CXCR4-expressing neutrophils migrated from the skin to the kidneys, where they subsequently underwent NETosis to release their pre-expressed cytokines and C3, thereby driving renal inflammation and injury. Genetic Cxcr4 deficiency impaired this inter-organ trafficking, attenuating renal neutrophil infiltration and proteinuria in UVB-irradiated kikGR;Cxcr4 +/- mice. Pharmacological CXCR4 inhibition further validated the therapeutic potential of blocking this migratory axis, attenuating lupus skin and kidney inflammation in UVB-irradiated lupus-prone mice. By linking environmental UVB exposure to systemic lupus outcomes through PKCα-driven nuclear envelope rupture for proinflammatory NET release and CXCR4-mediated neutrophil trafficking for systemic dissemination, this work provides strong mechanistic evidence for a skin-kidney axis in SLE. These findings identify nuclear envelope regulation and neutrophil trafficking as previously underexplored therapeutic targets for photosensitive SLE. SIGNIFICANCE This study explores a mechanistic skin-kidney axis in SLE, revealing a causal link between UVB-induced cutaneous inflammation and systemic disease exacerbations. We demonstrate that PKCα-driven nuclear envelope rupture is critical for the release of proinflammatory NETs, while CXCR4-mediated trafficking of non-NETting neutrophils represents a pivotal route for systemic dissemination. These findings delineate how neutrophils transition from local initiators of skin inflammation to systemic effectors of renal injury by propagating NET-driven inflammatory cascades. This work suggests a shift in the therapeutic paradigm toward precise regulation of neutrophil migration and NETosis kinetics. By uncovering these underexplored pathways, the study provides a molecular framework for intercepting UVB-induced systemic exacerbation in photosensitive SLE, with the potential to mitigate irreversible end-organ damage.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":415329,"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":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":870836,"name":"Minghui Li","orcid":"0009-0002-5443-3197","position":1,"is_corresponding":false},{"id":542650,"name":"Ping L. Zhang","orcid":"0000-0002-6177-9244","position":2,"is_corresponding":false},{"id":226321,"name":"Wei Wei","orcid":"0000-0003-1263-5620","position":4,"is_corresponding":false},{"id":273424,"name":"Victoria P. Werth","orcid":"0000-0003-3030-5369","position":5,"is_corresponding":false},{"id":273812,"name":"Ming‐Lin Liu","orcid":"0000-0001-8827-2024","position":6,"is_corresponding":false},{"id":655254,"name":"Xing Lyu","orcid":"0000-0002-9650-7492","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T01:22:12.933438Z","pmid":"38187639","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":[]}