Enhanced transcriptomic resilience following increased alternative splicing and differential isoform production between air pollution conurbations

Adverse health outcomes caused by ambient particulate matter (PM) pollution occur in a 16progressive process, with neutrophils eliciting inflammation or pathogenesis. We investigated the 17toxico-transcriptomic mechanisms of PM in real-life settings by comparing healthy residents living 18in Beijing and Chengde, the opposing ends of a well-recognised air pollution (AP) corridor in China. 19Beijing recruits (BRs) uniquely expressed ~12,000 alternative splicing (AS)-derived transcripts, 20largely elevating the proportion of transcripts significantly correlated with PM concentration. BRs 21expressed PM-associated isoforms (PMAIs) of PFKFB3 and LDHA, encoding enzymes responsible 22for stimulating and maintaining glycolysis. PMAIs of PFKFB3 featured different COOH-terminals, 23targeting PFKFB3 to different sub-cellular functional compartments and stimulating glycolysis. 24PMAIs of LDHA have longer 3’UTRs relative to those expressed in Chengde recruits (CRs),allowing 25glycolysis maintenance by enhancing LDHAmRNA stability and translational efficiency. PMAIs 26weredirectly regulated by different HIF-1Aand HIF-1Bisoforms. BRs expressed more non-func-27tional Fas isoforms and a resultant reduction of intact Fas proportion is expected to inhibit the trans-28mission of apoptotic signals and prolong neutrophil lifespan. BRs expressed both membrane-bound 29and soluble IL-6Risoforms instead of only one in CRs. The presence of both IL-6Risoforms sug-30gested a higher migration capacity of neutrophils in BRs. PMAIs of HIF-1Aand PFKFB3were down-31regulated in Chronic Obstructive Pulmonary Disease patients compared with BRs, implying HIF-1 32mediated defective glycolysis may mediate neutrophil dysfunction. PMAIs could explain large var-33iances of different phenotypes, highlighting their potential application as biomarkers and therapeu-34tic targets in PM-induced diseases, which remain poorly elucidated.