Endothelial cells line the inner surface of blood vessels, forming a selective barrier that controls the passage of cells and solutes between the blood and the parenchyma. Our group has found that the main cytokines involved in the inflammatory response regulate the expression and/or activation of the RhoA subfamily, composed of RhoA, RhoB, and RhoC, three GTPases with nearly identical sequences. Surprisingly, while RhoA and RhoB weaken the endothelial barrier by inducing actomyosin-mediated contraction and negatively regulating the formation of membrane extensions necessary for establishing adhesive contacts between cells (Marcos-Ramiro et al., JCB, 2016), RhoC preserves endothelial barrier function. While investigating the molecular basis of these opposing effects, we have artificially modulated the activity of these GTPases in the laboratory and reduced vascular hyperpermeability and tissue edema in preclinical models of septicemia (patent 201930571; Colás-Algora et al., ATVB, 2023, and manuscript in preparation).

Our research also extends to epithelial cells, where we have demonstrated the reciprocal relationship between the inflammatory response and the apicobasal polarity of hepatic epithelial barriers, mechanistically supported by the polarization and signaling capacity of the ICAM-1 adhesion receptor (Reglero-Real et al., Cell Rep, 2014, Cacho-Navas et al., CMLS, 2022). To demonstrate that this effect is independent of lymphocyte adhesion to these epithelia through this receptor, we have developed and cultured hepatic organoids in 3D from liver bipotent precursors (Cacho-Navas et al., eLife 2024).
Finally, the cornea is the paradigm of tissue organized into cellular barriers. In collaboration with the Jiménez Díaz Foundation and the Cornea Project company, we are investigating the organization of corneal endothelium and epithelium and their response to inflammatory and mechanical stress, searching for biomarkers of various ocular diseases.
In summary, cellular barriers are fundamental for compartmentalize functions such as transport, secretion or absorption in complex organisms. Our work in recent years have contributed to demonstrate the essential role that cellular barrier function also plays in regulating the inflammatory response, paving the way for finding new treatments for inflammatory diseases.