NLR proteins are a diverse family of pattern recognition receptors that are essential mediators of inflammation and host defense in the gastrointestinal system. Recent studies have identified a sub-group of inflammasome forming NLRs that modulate the mucosal immune response during inflammatory bowel disease (IBD) and colitis associated tumorigenesis. To better elucidate the contribution of NLR family members in IBD and cancer, we conducted a retrospective analysis of gene expression metadata from human patients. These data revealed that NLRP1, an inflammasome forming NLR, was significantly dysregulated in IBD and colon cancer. To better characterize the function of NLRP1 in disease pathogenesis, we utilized Nlrp1b−/− mice in colitis and colitis associated cancer models. Here, we report that NLRP1 attenuates gastrointestinal inflammation and tumorigenesis. Nlrp1b−/− mice demonstrated significant increases in morbidity, inflammation and tumorigenesis compared to wild type animals. Similar to data previously reported for related inflammsome forming NLRs, the increased inflammation and tumor burden was correlated with attenuated levels of IL-1β and IL-18. Further mechanistic studies utilizing bone marrow reconstitution experiments revealed that the increased disease pathogenesis in the Nlrp1b−/− mice was associated with non-hematopoietic derived cells and suggests that NLRP1 functions in the colon epithelial cell compartment to attenuate tumorigenesis. Together, these data identify NLRP1 as an essential mediator of the host immune response during IBD and cancer. These findings are consistent with a model whereby multiple NLR inflammasomes attenuate disease pathobiology through modulating IL-1β and IL-18 levels in the colon.

IC. Caspase-11 attenuates gastrointestinal inflammation and experimental colitis pathogenesis.

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.