Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier

Abstract

The nucleotide-binding domain and leucine-rich-repeat-containing family (NLRs) (sometimes called the NOD-like receptors, though the family contains few bona fide receptors) are a superfamily of multidomain-containing proteins that detect cellular stress and microbial infection. They constitute a critical arm of the innate immune response, though their functions are not restricted to pathogen recognition and members engage in controlling inflammasome activation, antigen-presentation, transcriptional regulation, cell death and also embryogenesis. NLRs are found from basal metazoans to plants, to zebrafish, mice and humans though functions of individual members can vary from species to species. NLRs also display highly wide-ranging tissue expression. Here, we discuss the importance of NLRs to the immune response at the epidermal barrier and summarise the known role of individual family members in the pathogenesis of skin disease.

Keywords: NLRs; inflammasome; keratinocyte; skin; skin disease.

Figure 1

The NLR superfamily. Schematic depicting the five subfamilies of human NLRs and their mouse orthologues. Additionally, depicted are protein structural domains, the known function of the NLRs, their expression in skin cells and association with skin diseases. AD, Acidic transactivating domain, BIR, baculovirus IAP repeat, CARD, caspase-activation and recruitment domain, FIIND, Function-to-find domain, FKLC, familial keratosis lichenoides chronica, IFN, Interferon, LRR, Leucine-rich repeats, MSPC, multiple self-healing palmoplantar carcinoma, NACHT, a domain found in NAIP, CIITA, HET-E and TEP1, ND, not determined. * Murine Naip3 lacks a NACHT-LRR and contains three BIR domains, Naip4 lacks a NACHT-LRR and contains one BIR domain, Naip5 & Naip6 lack an LRR region. # Murine Nlrp1a lacks a PYRIN, Nlrp1b lacks a PYRIN and FIIND, Nlrp1c lacks PYRIN, FIIND and CARD domains. † Murine Nlrp5 lacks a PYRIN domain. ‡ Murine Nlrp14 lacks a PYRIN domain. § Based on mRNA expression assessed by Reverse Transcriptase-PCR in human primary keratinocytes [15].

Figure 2

Expression and function of NLRs in human epidermis. (A) While inflammasome forming (NLRP1, NLRP3) and pro-inflammatory (NOD1, NOD2) NLRs are expressed in basal layers of the epidermis along with other pro-inflammatory genes, anti-inflammatory NLRs (NLRP10) and inflammasome inhibiting genes (CARD18) are rather enriched in the upper layers of the epidermis. (B) CIITA and NLRC5 are inducible in keratinocytes by IFN-γ and regulates MHC II and MHC I expression, respectively. NOD1 and NOD2 is activated by bacterial products, leading to NF-κB activation and inflamma Table 1. and NLRP3 are both forming inflammasomes in keratinocytes leading to IL-1β secretion NAIP, NLRP10 and NLRX1 are expressed in keratinocytes, however their functions in keratinocytes are not described so far. NLRP10 and NLRX1 were shown to inhibit NF-κB activity in professional immune cells and regulate inflammasome activation, however, whether these functions are dominant in keratinocytes is unknown.