Targeting monocytic Occludin impairs transendothelial migration and HIV neuroinvasion.

Transmigration of circulating monocytes from the bloodstream to tissues represents an early hallmark of inflammation. This process plays a pivotal role during viral neuroinvasion, encephalitis, and HIV-associated neurocognitive disorders. How monocytes locally unzip endothelial tight junction-associated proteins (TJAPs), without perturbing impermeability, to reach the central nervous system remains poorly understood. Here, we show that human circulating monocytes express the TJAP Occludin (OCLN) to promote transmigration through endothelial cells. We found that human monocytic OCLN (hmOCLN) clusters at monocyte-endothelium interface, while modulation of hmOCLN expression significantly impacts monocyte transmigration. Furthermore, we designed OCLN-derived peptides targeting its extracellular loops (EL) and show that transmigration of treated monocytes is inhibited in vitro and in zebrafish embryos, while preserving vascular integrity. Monocyte transmigration toward the brain is an important process for HIV neuroinvasion and we found that the OCLN-derived peptides significantly inhibit HIV dissemination to cerebral organoids. In conclusion, our study identifies an important role for monocytic OCLN during transmigration and provides a proof-of-concept for the development of mitigation strategies to prevent monocyte infiltration and viral neuroinvasion.

Evidence and therapeutic implications of biomechanically regulated immunosurveillance in cancer and other diseases.

Disease progression is usually accompanied by changes in the biochemical composition of cells and tissues and their biophysical properties. For instance, hallmarks of cancer include the stiffening of tissues caused by extracellular matrix remodelling and the softening of individual cancer cells. In this context, accumulating evidence has shown that immune cells sense and respond to mechanical signals from the environment. However, the mechanisms regulating these mechanical aspects of immune surveillance remain partially understood. The growing appreciation for the 'mechano-immunology' field has urged researchers to investigate how immune cells sense and respond to mechanical cues in various disease settings, paving the way for the development of novel engineering strategies that aim at mechanically modulating and potentiating immune cells for enhanced immunotherapies. Recent pioneer developments in this direction have laid the foundations for leveraging 'mechanical immunoengineering' strategies to treat various diseases. This Review first outlines the mechanical changes occurring during pathological progression in several diseases, including cancer, fibrosis and infection. We next highlight the mechanosensitive nature of immune cells and how mechanical forces govern the immune responses in different diseases. Finally, we discuss how targeting the biomechanical features of the disease milieu and immune cells is a promising strategy for manipulating therapeutic outcomes.

Platelets favor the outgrowth of established metastases.

Despite abundant evidence demonstrating that platelets foster metastasis, anti-platelet agents have low therapeutic potential due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subject syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases via immune suppression. Genetic depletion and pharmacological targeting of the glycoprotein VI (GPVI) platelet-specific receptor in humanized mouse models efficiently reduce the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study demonstrates therapeutic efficacy when targeting animals bearing growing metastases. It further identifies GPVI as a molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.