NOD-like receptors in autoimmune diseases

Abstract

Autoimmune diseases are chronic immune diseases characterized by dysregulation of immune system, which ultimately results in a disruption in self-antigen tolerance. Cumulative data show that nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) play essential roles in various autoimmune diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, multiple sclerosis (MS), etc. NLR proteins, consisting of a C-terminal leucine-rich repeat (LRR), a central nucleotide-binding domain, and an N-terminal effector domain, form a group of pattern recognition receptors (PRRs) that mediate the immune response by specifically recognizing cellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and triggering numerous signaling pathways, including RIP2 kinase, caspase-1, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and so on. Based on their N-terminal domain, NLRs are divided into five subfamilies: NLRA, NLRB, NLRC, NLRP, and NLRX1. In this review, we briefly describe the structures and signaling pathways of NLRs, summarize the recent progress on NLR signaling in the occurrence and development of autoimmune diseases, as well as highlight numerous natural products and synthetic compounds targeting NLRs for the treatment of autoimmune diseases.

Keywords: NOD-like receptors; autoimmune diseases; botanicals; inflammasomes; inhibitors; pattern recognition receptors.

Fig. 1. Protein structures of each NLR subfamily.

Human NLRs are divided into five subfamilies: NLRA, NLRB, NLRC, NLRP, and NLRX. All NLRs except NLRP10 contain an N-terminal effector domain, a central NACHT domain and a C-terminal LRR domain. CARD caspase recruitment domain, AD acidic transactivation domain, NACHT, NAIP (neuronal apoptosis inhibitor protein), CIITA (MHC class 2 transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein); BIR baculoviral inhibitory repeat-like domain, PYD pyrin domain, FIIND function to find domain, X unidentified, MTS mitochondria-localization sequence, LRR leucine-rich repeat

Fig. 2. Schematic representation of typical NLR signaling pathways.

Classic NLR signaling pathways are mainly composed of four parts: signal transduction, autophagy, transcriptional activation, and inflammasome activation. NOD1 and NOD2 recognize the bacterial peptidoglycans iE-DAP and MDP, respectively. Then, the NOD1/2 multimers are activated by homophilic CARD-CARD interactions to recruit the serine/threonine kinase RIP2 and form NOD signalosomes, which activate the NF-κB and MAPK signaling pathways. Autophagosomes deliver pathogens to lysosomes for degradation via the essential autophagic adapter proteins ATG5, ATG12 and ATG16L1, and ATG16L1 negatively regulates NOD/RIP2 signaling. NLRP2 and NLRP4 also negatively regulate activation of the NF-κB pathway by modifying TRAF6. IFN-γ stimulates CIITA and NLRC5 activation. Self-assembled CIITA and NLRC5 subsequently activate the transcription of MHCII and MHCI, respectively. Activated NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes recruit ASCs, followed by the activation of caspase-1, as well as the secretion of IL-1β and IL-18. In addition, the activation of caspase-1 also triggers pyroptosis

Fig. 3. The effect of NLRs on autoimmune diseases.

NLRs are involved in the development of multiple autoimmune diseases, including IBD, RA, SLE, psoriasis, MS, and T1D. Abnormal expression of NLRs and excessive inflammasome activation drive the pathogenesis of autoimmune diseases