Joshi_2026_Int.J.Mol.Sci_27_

Despite the critical role of lipid-mediated signaling in regulating host immunity, endorsed by growing evidence, the interaction between lipid metabolism and immune response remains largely unknown. This review aims to elucidate the immunomodulatory role of a lung-enriched lipid metabolic pathway mediated by the phospholipase A2 (PLA(2)) family, which comprises a diverse range of lipid-hydrolyzing enzymes. Based on their location, structure, substrate specificity and physiological roles, PLA(2)s can be classified into secreted PLA(2)s (sPLA(2)s), cytosolic PLA(2)s (cPLA(2)s), calcium-independent PLA(2)s (iPLA(2)s), and lysosomal-associated PLA(2)s (lPLA(2)s). These PLA(2) isoforms are similar in that they can all cleave cellular membrane-associated phospholipids, releasing free lysophospholipids and fatty acids such as arachidonic acid, which subsequently serve as precursors for a wide range of bioactive mediators responsible for physiological functions and pathological changes. Respiratory infections, especially those caused by bacteria and viruses, represent a substantial threat to the health of the population worldwide and cause billions of disease cases and millions of deaths annually. Respiratory infections provoke airway inflammation, characterized by increased vascular permeability and the influx of immune cells, resulting in tissue damage, impaired gas exchange, acute respiratory distress syndrome (ARDS) and even death. During infections and inflammatory milieu, airway-expressed PLA(2) can further increase and exhibit protection by restricting pathogens and inflammation or, in contrast, exacerbate the pathogenesis. In this manuscript, we will provide an overview of the current knowledge on the biological functions of PLA(2) isoforms, especially concerning membrane-associated isoforms in respiratory infections, and offer insight into the spatial and temporal regulation of immune responses mediated by PLA(2) and the subsequent modulation of host-pathogen interactions and the balance between protective effects and pathological outcomes.