The vasculature is a dynamic organ system essential not only for nutrient and oxygen delivery, fluid balance, and haemostasis, but also as a central regulator of immune surveillance and inflammatory responses. Endothelial cells (ECs), which line all blood and lymphatic vessels, serve as the interface between circulation and tissues and act as highly specialised immunoregulatory units. Beyond providing a physical barrier, ECs integrate mechanical, metabolic, and inflammatory cues from the tissue microenvironment to orchestrate immune cell trafficking, thereby shaping the balance between protective immunity and pathological inflammation (Nourshargh and Alon, 2014, Pober and Sessa, 2007, Amersfoort et al., 2022, Nourshargh et al., 2010).

Inflammation represents a coordinated host defence mechanism indispensable for survival and repair. However, excessive or unresolved inflammation can result in tissue damage and drive chronic disease (Medzhitov, 2008, Furman et al., 2019, Zhao et al., 2021). As key effector components of the inflammatory response, leukocytes are recruited from the bloodstream to the tissues following different inflammatory cues. This requires their sequential migration across postcapillary venules, involving breaching of ECs, pericytes, and the basement membrane (Nourshargh & Alon, 2014 ). EC activation is induced by a wide range of proinflammatory mediators, including cytokines (such as IL-6, IL-1β and TNF) and pathogen-associated molecular patterns (e.g. lipopolysaccharide: LPS), which are released by tissue resident cells (e.g. macrophages, dendritic cells and mast cells) or invading microorganisms, respectively. During steady state, ECs also enable selective trafficking of patrolling leukocytes in specific tissues, including the liver and lung, to maintain immune surveillance and homeostasis (Moreno-Cañadas et al., 2021, Ficht and Iannacone, 2020, Ballesteros et al., 2020). Beyond regulating trafficking, subsets of ECs display immune effector functions such as antigen presentation, T cell co-regulation, and phagocytosis (Amersfoort et al., 2022), consistent with their developmental link to immune cells (Lange et al., 2021).

The molecular events regulating leukocyte passage through vascular barriers have been extensively studied in postcapillary venules during inflammation and are described by the leukocyte adhesion cascade: rolling, arrest, crawling, and transendothelial migration (TEM) (Ley et al., 2007). This series of sequential but overlapping steps depends on selectins, chemokines, leukocyte β2-integrins and their counter-receptors in ECs (e.g. ICAM-1 and VCAM-1), and culminates in the reorganisation of EC junctional adhesion molecules (Woodfin et al., 2011, Colom et al., 2015, Girbl et al., 2018). EC junctions comprise tight junctions, which include members of the junctional adhesion molecule (JAM) family and claudins, adherent junctions (AJ) containing VE-cadherin and other molecules such as platelet endothelial cell adhesion molecule-1 (PECAM-1) (Dejana et al., 2009, Reglero-Real et al., 2016, Vestweber, 2015). TEM can occur via paracellular or transcellular routes, the latter particularly relevant at restrictive barriers such as the blood–brain barrier (BBB) (Mapunda et al., 2022). This highlights the need to study the molecular mechanisms regulating leukocyte TEM in different vascular beds, which might differ from the general dogma described above and impact the outcome of immune responses in different organs. Although other vascular and perivascular elements, including pericytes, the venular basement membrane, and resident sentinel cells, contribute to leukocyte guidance beyond the endothelial barrier (Proebstl et al., 2012, Voisin and Nourshargh, 2013, Pober and Tellides, 2012, Voisin et al., 2010, De Filippo et al., 2013), ECs remain key gatekeepers of leukocyte entry and thus central determinants of inflammatory responses (Nourshargh & Alon, 2014).

Over the last decade, autophagy has emerged as a central regulator of both innate and adaptive immunity (Deretic & Levine, 2018). Within leukocytes, autophagy regulates multiple immune cell functions, including cytokine production, differentiation, pathogen clearance and antigen presentation (Deretic, 2021). Consistent with this, genetic links between autophagy and inflammation have been identified across a wide spectrum of human disorders characterised by dysregulated immune responses (Deretic and Levine, 2018, Levine and Kroemer, 2019, Klionsky et al., 2021). At a cellular level, autophagy maintains intracellular homeostasis by delivering cytoplasmic material to lysosomes for degradation. This process encompasses the removal or recycling of protein aggregates, membranes, whole organelles such as mitochondria, and invading microorganisms, as well as the generation of metabolic substrates during nutrient stress (Herzig and Shaw, 2018, Lin and Hardie, 2018, Liu and Sabatini, 2020, Morishita and Mizushima, 2019).

Autophagy comprises several distinct but interconnected pathways. Macroautophagy, the best-characterised form and hereafter referred to as canonical autophagy, involves the sequestration of cytoplasmic material within double-membrane autophagosomes that subsequently fuse with lysosomes. This process is tightly regulated by autophagy-related genes (Atgs), including the ATG5–ATG12–ATG16L complex, which is essential for autophagosome initiation and elongation (Morishita and Mizushima, 2019, Feng et al., 2014, Yu et al., 2018). Upon autophagy induction, cytosolic microtubule-associated protein light chain 3B (LC3), a member of the ATG8 family, is lipidated and incorporated into the autophagosome double membrane. LC3-interacting regions then facilitate selective cargo recruitment, enabling delivery of autophagosomal contents to lysosomes for degradation (Morishita & Mizushima, 2019). Within canonical autophagy, both bulk and selective forms operate. Bulk autophagy involves the non-specific sequestration of portions of the cytoplasm, including organelles and macromolecular complexes, for degradation. By contrast, selective autophagy targets specific, potentially harmful cellular components for removal, often mediated by ubiquitination and cargo receptors. A prominent example is mitophagy, the selective degradation of damaged or dysfunctional mitochondria, which is essential for maintaining mitochondrial quality and overall cellular homeostasis (Vargas et al., 2023). In addition to canonical autophagy, microautophagy involves direct lysosomal membrane invagination of cytoplasmic material, while chaperone-mediated autophagy (CMA) selectively translocates individual proteins across the lysosomal membrane for degradation. Collectively, these forms of autophagy contribute to tissue homeostasis and immune regulation (Deretic, 2021, Kaushik et al., 2021, Macian, 2019).

Beyond these classical pathways, a growing number of non-canonical autophagy-related processes have been described. These mechanisms employ components of the canonical autophagy machinery but operate on single-membrane vesicles derived from the endocytic system (Galluzzi and Green, 2019, Galluzzi et al., 2017, Martinez-Martin et al., 2017). The prototypical example is LC3-associated phagocytosis (LAP), together with related pathways such as LC3-associated endocytosis (LANDO), collectively referred to as CASM (Conjugation of ATG8s to Single Membranes) (Sanjuan et al., 2007, Heckmann and Green, 2019, Heckmann et al., 2019, Florey et al., 2011). These pathways couple endolysosomal trafficking to LC3 lipidation and have important implications for immune cell activation and inflammatory regulation.

Within ECs, autophagy has long been recognised as a regulator of fundamental aspects of endothelial physiology, including survival, redox state, thrombosis, angiogenesis, and metabolism (Verhoeven et al., 2021, Nussenzweig et al., 2015, Sachdev and Lotze, 2017, Schaaf et al., 2019). More recently, EC autophagy has been directly implicated in the control of leukocyte trafficking, notably through effects on junctional organisation and adhesion molecule trafficking (Reglero-Real et al., 2021a). EC autophagy therefore emerges as a critical determinant of how immune cells access tissues. In this review, we focus on the role of EC autophagy in the regulation of immune cell functions, with particular emphasis on how EC autophagy shapes leukocyte entry into inflamed tissues (Table 1). We further discuss emerging evidence that EC autophagy influences a broader repertoire of immune processes, including pathogen clearance via xenophagy, tissue remodelling through phagocytosis and efferocytosis, antigen presentation in adaptive immunity, and the regulation of vascular function during ageing.