NOD1 and NOD2 are pattern recognition receptors of the innate immune system with well-established roles in sensing fragments of bacterial peptidoglycan. In addition to their role as microbial sensors, recent evidence indicates that nucleotide-binding oligomerization domains (NODs) can also recognize a broader array of danger signals. Indeed, recent work has expanded the roles of NOD1 and NOD2 to encompass not only sensing of infections with viruses and parasites but also perceiving perturbations of cellular processes such as regulation of the actin cytoskeleton and maintenance of endoplasmic reticulum homeostasis. This review will comment on recent progress and point out emerging questions in these areas.

Although viruses have long been known to subvert the endoplasmic reticulum (ER) for their replication, recent work has shown that this strategy is also used by bacterial pathogens and parasites to promote their intracellular growth. The ensuing disruption of cellular processes triggers a condition known as ER stress, which activates the host cell's unfolded protein response (UPR) to restore homeostasis. Recent work has linked the UPR, in particular the arm of this response that depends on the ER-resident sensor IRE1, to innate immunity and inflammation. Surprisingly, two intracellular innate immune receptors, NOD1 and NOD2, previously shown to sense bacterial peptidoglycan, were found to transduce ER stress signals to elicit inflammation. Given the known roles of both ER stress and NOD2 in chronic inflammatory diseases, including inflammatory bowel disease and type 2 diabetes, this new link has important implications for understanding the basis for these pathologies.

Although viruses have long been known to subvert the endoplasmic reticulum (ER) for their replication, recent work has shown that this strategy is also used by bacterial pathogens and parasites to promote their intracellular growth. The ensuing disruption of cellular processes triggers a condition known as ER stress, which activates the host cell's unfolded protein response (UPR) to restore homeostasis. Recent work has linked the UPR, in particular the arm of this response that depends on the ER-resident sensor IRE1, to innate immunity and inflammation. Surprisingly, two intracellular innate immune receptors, NOD1 and NOD2, previously shown to sense bacterial peptidoglycan, were found to transduce ER stress signals to elicit inflammation. Given the known roles of both ER stress and NOD2 in chronic inflammatory diseases, including inflammatory bowel disease and type 2 diabetes, this new link has important implications for understanding the basis for these pathologies.

The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses.IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.