Innate immunity confers an immediate nonspecific mechanism of microbial recognition through germ line-encoded pattern recognition receptors (PRRs). Of these, Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) have shaped our current understanding of innate regulation of adaptive immunity. It is now recognized that PRRs are paramount in instructing an appropriate adaptive immune response. Their ligands have been the focus of adjuvant research with the goal of generating modern vaccine combinations tailored to specific pathogens. In this review we will highlight the recent findings in the field of adjuvant research with a particular focus on the potential of TLR and NLR ligands as adjuvants and their influence on adaptive immune responses.

Key points •Nucleotide binding oligomerization domain (Nod)‐like receptors regulate cognition, anxiety and hypothalamic–pituitary–adrenal axis activation. •Nod‐like receptors regulate central and peripheral serotonergic biology. •Nod‐like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour. Abstract Gut–brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut–brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)‐like receptors (NLR), Nod1 and Nod2, as novel regulators for gut–brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress‐induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic–pituitary–adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell‐specific deletion of Nod1 (VilCre+Nod1f/f), but not Nod2, increased susceptibility to stress‐induced anxiety‐like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut–brain communication and may serve as potential novel therapeutic targets for the treatment of gut–brain disorders.

The mitochondrial Nod-like receptor protein NLRX1 protects against colorectal tumorigenesis through mechanisms that remain unclear. Using mice with an intestinal epithelial cells (IEC)-specific deletion of Nlrx1, we find that NLRX1 provides an IEC-intrinsic protection against colitis-associated carcinogenesis in the colon. These Nlrx1 mutant mice have increased expression of Tnf, Egf, and Tgfb1, three factors essential for wound healing, as well as increased epithelial proliferation during the epithelial regeneration phase following injury triggered by dextran sodium sulfate. In primary intestinal organoids lacking Nlrx1, stimulation with TNF resulted in exacerbated proliferation and expression of the intestinal stem cell markers Olfm4 and Myb. This hyper-proliferation response was associated with increased activation of Akt and NF-κB pathways in response to TNF stimulation. Together, these results identify NLRX1 as a suppressor of colonic tumorigenesis that acts by controlling epithelial proliferation in the intestine during the regeneration phase following mucosal injury.

Highlights d Nod1 affects MDSC expansion and alternative reprogramming of macrophages d Nod1-mediated autophagy regulates arginase-1 levels in macrophages and MDSCs d Myeloid-specific Nod1 signaling modulates T cell suppression via arginase-1 d Myeloid Nod1 shapes the tumor microenvironment to promote colorectal cancer

BackgroundThe intestinal epithelium plays a critical role in nutrient absorption and innate immune defense. Recent studies showed that metabolic stress pathways, in particular the integrated stress response (ISR), control intestinal epithelial cell fate and function. Here, we used RNA-seq to analyze the global transcript level and alternative splicing responses of primary murine enteroids undergoing two distinct ISR-triggering stresses, endoplasmic reticulum (ER) stress and nutrient starvation.ResultsOur results reveal the core transcript level response to ISR-associated stress in murine enteroids, which includes induction of stress transcription factors, as well as genes associated with chemotaxis and inflammation. We also identified the transcript expression signatures that are unique to each ISR stress. Among these, we observed that ER stress and nutrient starvation had opposite effects on intestinal stem cell (ISC) transcriptional reprogramming. In agreement, ER stress decreased EdU incorporation, a marker of cell proliferation, in primary murine enteroids, while nutrient starvation had an opposite effect. We also analyzed the impact of these cellular stresses on mRNA splicing regulation. Splicing events commonly regulated by both stresses affected genes regulating splicing and were associated with nonsense-mediated decay (NMD), suggesting that splicing is modulated by an auto-regulatory feedback loop during stress. In addition, we also identified a number of genes displaying stress-specific splicing regulation. We suggest that functional gene expression diversity may arise during stress by the coordination of alternative splicing and alternative translation, and that this diversity might contribute to the cellular response to stress.ConclusionsTogether, these results provide novel understanding of the importance of metabolic stress pathways in the intestinal epithelium. Specifically, the importance of cellular stresses in the regulation of immune and defense function, metabolism, proliferation and ISC activity in the intestinal epithelium is highlighted. Furthermore, this work highlights an under-appreciated role played by alternative splicing in shaping the response to stress and reveals a potential mechanism for gene regulation involving coupling of AS and alternative translation start sites.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2999-1) contains supplementary material, which is available to authorized users.