The role of phospholipase D4 in inflammatory autoimmune diseases

Phospholipase D4 (PLD4) represents a highly specialised lysosomal 5´-to-3´ exonuclease functioning as a definitive molecular checkpoint governing innate immune homeostasis. Although structurally classified within the classical phospholipase D family, PLD4 is entirely devoid of lipid hydrolytic capacity, instead executing rigorous enzymatic degradation of sequestered single-stranded DNA and RNA. By strictly orchestrating the structural clearance of these localised nucleic acid ligands, this unique enzyme fundamentally restrains the aberrant hyperactivation of critical pattern recognition pathways, specifically Toll-like receptors 7 and 9. Consequently, genetic polymorphisms and profound transcriptional dysregulation of PLD4 actively drive a spectrum of severe systemic autoimmune pathologies, prominently encompassing systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.This review systematically synthesises the precise molecular mechanisms dictating PLD4-mediated immunomodulation, elucidating its profound impact on cellular phenotypic plasticity and localised inflammatory cytokine cascades. Ultimately, we provide a rigorous translational framework contextualising PLD4 not merely as a fundamental biological regulator, but as a highly actionable therapeutic target for neutralising refractory inflammatory autoimmune diseases.