Autophagy, endolysosomes and extracellular space in autoimmune and innate immune defects

Autophagy is increasingly recognized as a central immunological process whose roles extend far beyond intracellular recycling. By coordinating lysosomal degradation, organelle quality control, selective antimicrobial clearance, and inflammatory signal termination, autophagy acts as a decisive checkpoint at the crossroads between protective innate immunity and pathological immune persistence. Xenophagy, the selective autophagic elimination of intracellular pathogens, is a particularly important process at the interface between host defense, endosomal trafficking and immune resolution. Distinct monogenic disorders affecting EPG5-dependent autophagosome-lysosome fusion, LYST-dependent lysosomal and granule organization, or RAB27A-dependent lytic-granule exocytosis illustrate how different lesions in intracellular trafficking can impair microbial handling and contribute to immune dysregulation. Functioning autophagy also boosts cellular resilience through the removal of intracellular debris via exocytosis. In parallel, neutrophil extracellular traps (NETs) have emerged as potent antimicrobial structures that also aid cellular resilience but have a dual role in immunity: while NET formation can restrict pathogen dissemination, excessive or insufficiently cleared NETs expose chromatin, histones, proteases and modified autoantigens that can drive autoimmunity, thromboinflammation and tissue damage. In this review, we discuss the intricate links between xenophagy, its intracellular endolysosomal hubs, and its extracellular targets and traps as an integrated cell-biological and immunopathological network. We highlight how autophagy initiation and verified degradative flux, mitochondrial quality control, reactive oxygen species, peptidylarginine deiminase 4 (PAD4)-dependent chromatin decondensation, and endolysosomal trafficking may intersect with neutrophil effector functions in a stimulus- and model-dependent manner. Particular emphasis is placed on endosomal checkpoint proteins such as TOM1, which link ubiquitinated cargo sorting, IL-1R1/NF-κB signal termination, autophagosome maturation, and lysosomal degradation. We propose that defective endosomal and autophagic resolution mechanisms blur the boundary between efficient antimicrobial defense and chronic inflammatory auto-amplification. This concept is highly relevant for a wide range of autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, ANCA-associated vasculitis, autoinflammatory syndromes, immunodeficiency, and neuroinflammatory disease. Finally, we discuss therapeutic strategies aimed at restoring immune resolution, including modulation of autophagy, enhancement of NET clearance, targeting of PAD4 and inflammasome pathways as well as correction of endolysosomal trafficking defects. Understanding these intricately linked networks may open new avenues for mechanism-based treatment of autoimmune and innate immune disorders.