Enhanced Transcriptomic Resilience following Increased Alternative Splicing and Differential Isoform Production between Air Pollution Conurbations

Abstract

Adverse health outcomes caused by ambient particulate matter (PM) pollution occur in a progressive process, with neutrophils eliciting inflammation or pathogenesis. We investigated the toxico-transcriptomic mechanisms of PM in real-life settings by comparing healthy residents living in Beijing and Chengde, the opposing ends of a well-recognised air pollution (AP) corridor in China. Beijing recruits (BRs) uniquely expressed ~12,000 alternative splicing (AS)-derived transcripts, largely elevating the proportion of transcripts significantly correlated with PM concentration. BRs expressed PM-associated isoforms (PMAIs) of PFKFB3 and LDHA, encoding enzymes responsible for stimulating and maintaining glycolysis. PMAIs of PFKFB3 featured different COOH-terminals, targeting PFKFB3 to different sub-cellular functional compartments and stimulating glycolysis. PMAIs of LDHA have longer 3′UTRs relative to those expressed in Chengde recruits (CRs), allowing glycolysis maintenance by enhancing LDHA mRNA stability and translational efficiency. PMAIs were directly regulated by different HIF-1A and HIF-1B isoforms. BRs expressed more non-functional Fas isoforms, and a resultant reduction of intact Fas proportion is expected to inhibit the transmission of apoptotic signals and prolong neutrophil lifespan. BRs expressed both membrane-bound and soluble IL-6R isoforms instead of only one in CRs. The presence of both IL-6R isoforms suggested a higher migration capacity of neutrophils in BRs. PMAIs of HIF-1A and PFKFB3 were downregulated in Chronic Obstructive Pulmonary Disease patients compared with BRs, implying HIF-1 mediated defective glycolysis may mediate neutrophil dysfunction. PMAIs could explain large variances of different phenotypes, highlighting their potential application as biomarkers and therapeutic targets in PM-induced diseases, which remain poorly elucidated.