Regulation of immune pathways by the NOD-like receptor NLRC5

Abstract

Members of the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family are quickly emerging as critical regulators of innate and adaptive immune responses during microbial infection and autoimmunity. The NLR family member NLRC5 was recently proposed to function as a positive and negative regulator of antiviral immune responses. NLRC5 has also been implicated in regulation of inflammasome signaling and MHC class I transcription. Some of these functions have recently been assessed in NLRC5-deficient mice and immune cells. Here, we summarize and review the newly gained knowledge on the structure, expression profile and putative functions of NLRC5 in regulating immune responses and host defense.

Introduction

The innate immune system recognizes infections and cellular damage through a limited number of pattern recognition receptors (PRRs) (Kawai and Akira, 2006, Kumar et al., 2009). PRRs are thought to sense conserved microbial components that are vital for microbial survival such as flagellin and nucleic acid structures unique to bacteria and viruses (Akira et al. 2006). It is increasingly recognized that PRRs may also probe the environment for endogenous danger-associated molecular patterns (DAMPs) such as uric acid and HMGB1, which are produced or released upon tissue damage during infection or as a consequence of physicochemical stress. PRR activation triggers a number of protective responses, including the production of pro-inflammatory cytokines and chemokines that are responsible for activation of phagocytes and the recruitment of neutrophils, NK cells and lymphocytes to the site of infection. Moreover, innate immune responses contribute to adaptive immunity by instructing lymphocytes to mount T helper and humoral responses through the presentation of immunogenic peptides on MHC class I and class II receptors of professional antigen-presenting cells (Kanneganti et al. 2007).

Several PRR families can be distinguished, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), HIN-200 proteins and nucleotide binding and oligomerization domain-like receptors (NLRs) (Inohara et al., 2005, Kanneganti et al., 2007, Lamkanfi and Dixit, 2009, Meylan and Tschopp, 2006). Much research in recent years has focussed on characterizing the roles and signaling pathways of NLR family members in regulating the immune response. Bioinformatics studies revealed the existence of 22 human NLR genes and recent gene duplications gave rise to 34 mouse NLRs (Kanneganti et al. 2007). These platform proteins are characterized by the presence of a conserved nucleotide binding and oligomerization domain (referred to as NBD; NOD or NACHT domain) and located in intracellular compartments. Notably, the architecture of NLRs resembles that of a subset of plant disease-resistance (R) genes, which are involved in the hypersensitive response against virulent plant pathogens (Inohara and Nunez, 2001, Lamkanfi and Dixit, 2009). NLRs are involved in a multitude of innate immune signaling pathways ranging from the regulation of MAP kinase and NF-κB signaling pathways for Nod1 and Nod2, over modulation of MHC class II genes for CIITA, to the assembly of caspase-1-activating protein complexes named ‘inflammasomes’ for the NLR proteins NLRP1, NLRP3 and NLRC4 (Kanneganti et al., 2007, Lamkanfi and Dixit, 2009). Interestingly, the recently identified NLR family member NLRC5 (also known as NOD27, FLJ21709 and CLR16.1) has been suggested to regulate each of these signaling pathways. Moreover, NLRC5 deficient mice have been generated and used to examine the physiological role of this NLR in regulating immune responses and host defense during bacterial and viral infection in vivo. The recently gained knowledge on the expression, immune roles and signaling pathways of NLRC5 is summarized and critically reviewed in the following paragraphs.