Functions of NOD-Like Receptors in Human Diseases

Abstract

Nucleotide-binding and oligomerization domain NOD-like receptors (NLRs) are highly conserved cytosolic pattern recognition receptors that perform critical functions in surveying the intracellular environment for the presence of infection, noxious substances, and metabolic perturbations. Sensing of these danger signals by NLRs leads to their oligomerization into large macromolecular scaffolds and the rapid deployment of effector signaling cascades to restore homeostasis. While some NLRs operate by recruiting and activating inflammatory caspases into inflammasomes, others trigger inflammation via alternative routes including the nuclear factor-κB, mitogen-activated protein kinase, and regulatory factor pathways. The critical role of NLRs in development and physiology is demonstrated by their clear implications in human diseases. Mutations in the genes encoding NLRP3 or NLRP12 lead to hereditary periodic fever syndromes, while mutations in CARD15 that encodes NOD2 are linked to Crohn's disease or Blau's syndrome. Genome-wide association studies (GWASs) have identified a number of risk alleles encompassing NLR genes in a host of diseases including allergic rhinitis, multiple sclerosis, inflammatory bowel disease, asthma, multi-bacillary leprosy, vitiligo, early-onset menopause, and bone density loss in elderly women. Animal models have allowed the characterization of underlying effector mechanisms in a number of cases. In this review, we highlight the functions of NLRs in health and disease and discuss how the characterization of their molecular mechanisms provides new insights into therapeutic strategies for the management of inflammatory pathologies.

Keywords: IBD; NLR; autoimmunity; infection; inflammation; innate immunity; polymorphisms; reproduction.

Figure 1

The human NLR gene family. The human NLR gene family consists of 22 members that share a tripartite structure, consisting of an N-terminal signaling domain, a central nucleotide-binding and oligomerization domain, and a C-terminal agonist sensing/ligand-binding domain. The NLR family is sub-divided into four sub-groups NLRA, NLRB, NLRC, and NLRP based on the nature of the N-terminal domain consisting respectively of an acidic transactivation domain, a baculovirus IAP repeat (BIR), a caspase-recruitment and activation domain (CARD), and a Pyrin domain (PYD).

Figure 2

The NLR inflammasomes. The three biochemically characterized inflammasomes are depicted. The NLRP1 inflammasome consists of NLRP1, ASC, and caspases-1 and -5. Little is known about the agonists that activate NLRP1. Anthrax lethal toxin, MDP, and decreased cytosolic ATP have been reported to stimulate this inflammasome. NAIP and NLRC4 form a caspase-1 inflammasome in response to bacterial flagellin and T3SS rod proteins. NLRP3, on the other hand, is activated by a wide range of agonists including a number of MAMPs and DAMPs.

Figure 3

NOD-like receptors and disease. NLRs have been implicated in a plethora of diseases. Genetic studies have uncovered a number of variants in genes encoding NLRs or their signaling mediators associated with human diseases. Animal models have served as a key discovery platform to characterize the underlying functions and molecular mechanisms of NLRs in these diseases and associated pathologies. Together, these efforts have led to therapeutic success in the clinic for a subset of NLR-dependent auto-inflammatory diseases. When available, the mutations and SNPs linked to disease are listed and animal phenotypes are presented.

Figure 3

NOD-like receptors and disease. NLRs have been implicated in a plethora of diseases. Genetic studies have uncovered a number of variants in genes encoding NLRs or their signaling mediators associated with human diseases. Animal models have served as a key discovery platform to characterize the underlying functions and molecular mechanisms of NLRs in these diseases and associated pathologies. Together, these efforts have led to therapeutic success in the clinic for a subset of NLR-dependent auto-inflammatory diseases. When available, the mutations and SNPs linked to disease are listed and animal phenotypes are presented.

Figure 4

NOD1/2 signaling pathways. The NOD1 and 2 receptors recognize the bacterial peptidoglycan derivatives DAP and MDP. The events involved in signal transduction are depicted and involve the formation of a nodosome complex that is stabilized through a series of ubiquitin scaffolds mediated by a number of E3 ligases including cIAP1/2, XIAP, LUBAC, and ITCH. These scaffolds serve to engage effector kinases, including TAK1 and the IKK complex to activate NF-κB and MAPK pathways. NOD2 is additionally activated by single-stranded RNA viruses and stimulates an antiviral innate immune response by engaging MAVS and activating IRF3. The NOD receptors have also been shown to synergize with NLRP sensors to activate the inflammasome. Conversely, they have also been implicated in triggering autophagy though association with ATG16L1, and in response to viral infection, to inhibit the inflammasome by upregulating ULK1-dependent mitophagy.