Activated platelets cause microvascular inflammation via direct activation of perivascular mast cells.

Objective: Cardiac surgery, especially when employing cardiopulmonary bypass and deep hypothermic circulatory arrest, is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that mast cells are activated in a microenvironment shaped by intestinal ischemia/reperfusion, and investigated local and systemic consequences. Design: Rat model of deep hypothermic circulatory arrest. Setting: University research laboratory. Subjects: Twelve- to 14-week-old male Sprague–Dawley rats. Interventions: Rats were anesthetized and cooled to 16°C to 18°C on cardiopulmonary bypass before instituting deep hypothermic circulatory arrest for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery. Measurements and Main Results: Significant intestinal barrier disruption was found, together with macro- and microscopic evidence of ischemia/reperfusion injury in ileum and colon, but not in the lungs or kidneys. Immunofluorescence and toluidine blue staining revealed increased numbers of mast cells and their activation in the gut. In animals pretreated with the mast cell stabilizer, cromolyn sodium, mast cell degranulation was blocked, and intestinal morphology and barrier function were preserved following deep hypothermic circulatory arrest. Furthermore, cromolyn sodium treatment was associated with reduced intestinal neutrophil influx and blunted systemic release of proinflammatory cytokines. Conclusion: Our data provide primary evidence that intestinal ischemia/reperfusion is a leading pathophysiologic process in a rat model of deep hypothermic circulatory arrest, and that intestinal injury, and local and systemic inflammatory responses are critically dependent on mast cell activation. This identifies intestinal mast cells as central players in deep hypothermic circulatory arrest–associated responses, and opens novel therapeutic possibilities for patients undergoing this procedure.

Conjugation with the small ubiquitin-like modifier (SUMO) constitutes a key post-translational modification regulating the stability, activity, and subcellular localization of its target proteins. However, the vast numbers of identified SUMO substrates obscure a clear view on the function of SUMOylation in health and disease. This article presents a comprehensive review on the physiological relevance of SUMOylation by discussing how global SUMOylation levels—rather than specific protein SUMOylation—shapes the immune response. In particular, we highlight the growing body of work on SUMOylation in intestinal pathologies, because of the unique metabolic, infectious, and inflammatory challenges of this organ. Recent studies show that global SUMOylation can help restrain detrimental inflammation while maintaining immune defenses and tissue integrity. These results warrant further efforts to develop new therapeutic tools and strategies to control SUMOylation in infectious and inflammatory disorders.

Inflammatory bowel diseases (IBDs) are chronic debilitating conditions without cure, the etiologies of which are unknown, that shorten the lifespans of 7 million patients worldwide by nearly 10%. Here, we found that decreased autonomic parasympathetic tone resulted in increased IBD susceptibility and mortality in mouse models of disease. Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10/α7 nicotinic cholinergic vagal pathway. Colonic biopsies from patients with IBDs and mouse models showed an increase in small ubiquitin-like modifier (SUMO)2 and SUMO3 during active disease. In global genetic knockout mouse models, the deletion of Sumo3 protected against development of colitis and delayed onset of disease, whereas deletion of Sumo1 halted the progression of colitis. Bone marrow transplants from Sumo1 -knockout (KO) but not Sumo3 -KO mice into wild-type mice conferred protection against development of colitis. Electric stimulation of the cervical vagus nerve before the induction of colitis inhibited SUMOylation and delayed the onset of colitis in Sumo1 -KO mice and resulted in milder symptoms in Sumo3 -KO mice. Treatment with TAK-981, a first-in-class inhibitor of the SUMO-activating enzyme, ameliorated disease in three murine models of IBD and reduced intestinal permeability and bacterial translocation in a severe model of the disease, suggesting the potential to reduce progression to sepsis. These results reveal a pathway of vagal neuromodulation that reprograms endogenous stress-adaptive responses through inhibition of SUMOylation and suggest SUMOylation as a therapeutic target for IBD.

Mast cells (MCs) are present in various tissues and are responsible for initiating many of the early inflammatory responses to extrinsic challenges. Recent studies have demonstrated that MCs can tailor their responses, depending on the stimulus encountered and the tissue in which they are stimulated. In this issue of the JCI, Gaudenzio and colleagues examine the mechanistic differences between MC responses observed after engagement of Fcε receptor I and those seen after MC stimulation via the recently identified G protein–coupled receptor MRGPRX2. By showing that discrete cellular activation patterns affect the phenotype of the MC response in vivo and in vitro, the authors provide important information about how MCs differentially process various stimuli into distinct degranulation programs.