IQGAP2 regulates blood-brain barrier immune dynamics.

Brain endothelial cells (BECs) play an important role in maintaining central nervous system (CNS) homeostasis through blood-brain barrier (BBB) functions. BECs express low baseline levels of adhesion receptors, which limits entry of leukocytes. However, the molecular mediators governing this phenotype remain mostly unclear. Here, we explored how infiltration of immune cells across the BBB is influenced by the scaffold protein IQ motif containing GTPase activating protein 2 (IQGAP2). In mice and zebrafish, we demonstrate that loss of Iqgap2 increases infiltration of peripheral leukocytes into the CNS under homeostatic and inflammatory conditions. Using single-cell RNA sequencing and immunohistology, we further show that BECs from mice lacking Iqgap2 exhibit a profound inflammatory signature, including extensive upregulation of adhesion receptors and antigen-processing machinery. Human tissue analyses also reveal that Alzheimer's disease is associated with reduced hippocampal IQGAP2. Overall, our results implicate IQGAP2 as an essential regulator of BBB immune privilege and immune cell entry into the CNS.

IL-17 receptor A functions to help maintain barrier integrity and limit activation of immunopathogenic response to H. pylori infection.

Activation of Th17 cell responses, including the production of IL-17A and IL-21, contributes to host defense and inflammatory responses by coordinating adaptive and innate immune responses. IL-17A and IL-17F signal through a multimeric receptor, which includes the IL-17 receptor A (IL-17RA) subunit and the IL-17RC subunit. IL-17RA is expressed by many cell types, and data from previous studies suggest that loss of IL-17 receptor is required to limit immunopathology in the Helicobacter pylori model of infection. Here, an Il17ra-/- mouse was generated on the FVB/n background, and the role of IL-17 signaling in the maintenance of barrier responses to H. pylori was investigated. Generating the Il17ra-/- on the FVB/n background allowed for the examination of responses in the paragastric lymph node and will allow for future investigation into carcinogenesis. While uninfected Il17ra-/- mice do not develop spontaneous gastritis following H. pylori infection, Il17ra-/- mice develop severe gastric inflammation accompanied by lymphoid follicle production and exacerbated production of Th17 cytokines. Increased inflammation in the tissue, increased IgA levels in the lumen, and reduced production of Muc5ac in the corpus correlate with increased H. pylori-induced paragastric lymph node activation. These data suggest that the cross talk between immune cells and epithelial cells regulates mucin production, IgA production, and translocation, impacting the integrity of the gastric mucosa and therefore activating of the adaptive immune response.