SummaryThe endothelial barrier of the vasculature is of utmost importance for separating the blood stream from underlying tissues. This barrier is formed by tight and adherens junctions (TJ and AJ) that form intercellular endothelial contacts. TJ and AJ are integral membrane structures that are connected to the actin cytoskeleton via various adaptor molecules. Consequently, the actin cytoskeleton plays a crucial role in regulating the stability of endothelial cell contacts and vascular permeability. While a circumferential cortical actin ring stabilises junctions, the formation of contractile stress fibres, e. g. under inflammatory conditions, can contribute to junction destabilisation. However, the role of actin-binding proteins (ABP) in the control of vascular permeability has long been underestimated. Naturally, ABP regulate permeability via regulation of actin remodelling but some actin-binding molecules can also act independently of actin and control vascular permeability via various signalling mechanisms such as activation of small GTPases. Several studies have recently been published highlighting the importance of actin-binding molecules such as cortactin, ezrin/ radixin/moesin, Arp2/3, VASP or WASP for the control of vascular permeability by various mechanisms. These proteins have been described to regulate vascular permeability under various pathophysiological conditions and are thus of clinical relevance as targets for the development of treatment strategies for disorders that are characterised by vascular hyperpermeability such as sepsis. This review highlights recent advances in determining the role of ABP in the control of endothelial cell contacts and vascular permeability.

Cancer is a major cause of death in children worldwide, with B-lineage cell acute lymphoblastic leukemia (B-ALL) being the most frequent childhood malignancy. Relapse, treatment failure and organ infiltration worsen the prognosis, warranting a better understanding of the implicated mechanisms. Cortactin is an actin-binding protein involved in cell adhesion and migration that is overexpressed in many solid tumors and in adult B-cell chronic lymphocytic leukemia. Here, we investigated cortactin expression and potential impact on infiltration and disease prognosis in childhood B-ALL. B-ALL cell lines and precursor cells from bone marrow (BM) and cerebrospinal fluid (CSF) of B-ALL patients indeed overexpressed cortactin. In CXCL12-induced transendothelial migration assays, transmigrated B-ALL cells had highest cortactin expression. In xenotransplantation models, only cortactinhigh-leukemic cells infiltrated lungs, brain, and testis; and they colonized more easily hypoxic BM organoids. Importantly, cortactin-depleted B-ALL cells were significantly less efficient in transendothelial migration, organ infiltration and BM colonization. Clinical data highlighted a significant correlation between high cortactin levels and BM relapse in drug-resistant high-risk B-ALL patients. Our results emphasize the importance of cortactin in B-ALL organ infiltration and BM relapse and its potential as diagnostic tool to identify high-risk patients and optimize their treatments.

Innate lymphoid cells (ILC) are members of a heterogeneous family with a lymphoid origin that mimics the T helper (Th) cytokine profile. ILC are involved in early effector cytokine-mediated responses during infections in peripheral tissues. ILC also play an important role in chronic skin inflammatory diseases, including psoriasis. Although classical ILC express CD127, it has been recently reported that the presence of non-classical CD127− ILC populations and an early ILC precursor (EILP) CD127low. ILC development has predominately been investigated in mouse models. However, in humans, different transcription factors have been described for ILC identification. NFIL3 (nuclear factor, IL-3 regulated) is crucial for ILC development in response to IL-7. CD123 (IL-3Rα) is usually used to exclude basophils during ILC identification, however, it is unknown if in response to IL-3, NFIL3 could be relevant to induce ILC features in Lin− CD123+ populations in addition, is also unknown whether peripheral blood (PB) population with ILC features may have skin-homing potential to participate in skin inflammatory chronic diseases. Here, we report a Lin− CD123+ CD127low CD7+ CLA+ population that share some phenotypic properties with basophils, but expresses several transcription factors for ILC commitment such as inhibitor of DNA binding 2 (Id2), NFIL3, promyelocytic leukemia zinc finger (PLZF), thymocyte selection-associated high-mobility group box protein (TOX), and T cell factor-1 (TCF-1). In addition, this population expresses different ILC markers: CD132, CD90, CD161, α4 integrin, c-Kit, CRTH2, AhR, and IL-23R. IL-3 prevents apoptosis and increases their NFIL3, TOX, and PLZF expression. In PB, the CD123+ CD127low population is predominantly a conspicuous population that expresses T-bet and RORγt. The Lin− CD123+ CD127low population in PB has a limited Th type cytokine expression and highly expresses IL-8. The Lin− CD123+ CD127low population expresses skin-homing receptors (cutaneous lymphocyte antigen and CXCR4) and transmigrates through endothelial cells in response to SDF-1. An equivalent Lin− CD123low population was identified in control skin, which shows a broader phenotypic diversity and cytokine production, including IL-22 and IL-17. Remarkably, the CD123low population in the lesion and non-lesion skin of psoriasis patients expresses IL-17 and IL-22. Our findings suggest the identification of an alternative Lin− CD123+ CD127low population with ILC features endowed with migratory capabilities that might contribute to immunopathological hallmarks of psoriasis.