Effector functions of NLRs in the intestine: innate sensing, cell death, and disease

Nucleotide-binding and oligomerization domain-like receptors (NLRs) are central regulators of pathogen recognition, the induction of innate immune effectors and inflammation with utmost importance in human diseases such as inflammatory bowel diseases. Most NLRs are key mediators of inflammasome complexes that activate caspase-1 and drive proteolytic processing of pro-inflammatory cytokines; however, a few tightly regulate inflammasome-independent activation of nuclear factor-κB and mitogen-activated protein kinase pathways. NLR signaling has evolved in intestinal epithelial cells to avoid overactive inflammatory responses toward the resident microbiota and to preserve epithelial barrier integrity and functions by maintaining homeostasis. In the present review, I examine new insights into the role of the NLRs in antimicrobial defenses. I pay particular attention to the emerging role of these receptors in engaging a complex cross talk between cell death and innate immunity pathways. Furthermore, I discuss the physiological functions of the NLRs in shaping the innate immune response within the intestine, maintaining homeostasis, inducing tissue repair following injury and promoting tumorigenesis.