NLRs join TLRs as innate sensors of pathogens

Pathogen-recognition receptors (PRRs) are key components of immune systems and are involved in innate effector mechanisms and activation of adaptive immunity. Since their discovery in vertebrates, Toll-like receptors (TLRs) have become the focus of extensive research that has revealed their significance in the regulation of many facets of our immune system. What makes TLRs so central and fascinating is their ability to recognize microbes and directly initiate specific signal transduction cascades that alert the host defences. In this review, we discuss the function and biology of a new family of PRRs, the NACHT-LRRs (NLRs), which include both nucleotide-binding oligomerization domains (NODs) and NALPs [NACHT-, LRR- and pyrin domain (PYD)-containing proteins], and underline some intriguing similarities between NLRs and TLRs that emphasize the role of NLRs as a complementary system for host–microbe interactions.

Introduction

Innate immunity was thought formerly to be a non-specific immune response characterized by engulfment and digestion of microorganisms and foreign substances by macrophages and leukocytes. However, innate immunity acts with substantial specificity and is adept at discrimination between pathogens and self. Since the early nineties, Charles Janeway and his collaborators have proposed that the innate immune system can recognize key molecular signatures borne by pathogens, called pathogen-associated molecular patterns (PAMPs) [1]. These patterns represent molecules vital for microbial survival and are therefore unlikely to vary in their structures because any major changes would be disadvantageous. Such molecules include bacterial structural components, such as lipopolysaccharide (LPS) and peptidoglycans (PGNs), or viral RNA. Janeway predicted that host organisms develop a group of receptors that recognize these PAMPs, referred to as pathogen-recognition receptors (PRRs).

PAMPs are not the only trigger of innate immunity. Innate immunity can recognize abnormal self or danger signals, such as DNA, RNA or uric acid, which should not normally be present outside cells or at certain locations within the cell 2, 3. This proposed mechanism, also known as the ‘danger model’, is well illustrated in the case of the high mobility group box 1 (HMGB1) protein, a nuclear factor and secreted protein. In the cell nucleus, HMGB1 acts as an architectural chromatin-binding factor; however, outside the cell, it binds to RAGE (receptor for advanced glycation end-products), activates TLRs and is a potent mediator of inflammation 4, 5. Although the models of recognition of pathogen molecular patterns and the ‘danger model’ often appear to be opposed, they are not mutually exclusive because both systems might be necessary and might use the same collection of PRRs, converging on the same basic mechanism of activating inflammation and the adaptive immune system.

The activation of PRRs can lead to mobilization of soluble defence molecules, killing of the infected cells or tissues, acquisition of specialized functions by sentinel cells, induction of co-stimulatory molecules by antigen-presenting cells, and many other physiological responses. One of the modes of action of PRRs is the transcription activation [e.g. by the NF-κB or interferon-β (IFN-β) pathway], resulting in mobilization of the effectors of inflammation. Several of these PRRs have been identified; Toll-like receptors (TLRs) being the most studied [6]. Being transmembrane receptors, TLRs survey the extracellular fluids, including endosomal compartments, and have an important role in cross-presentation of particular pathogens to lymphocytes [7] (for more detailed information on TLRs, excellent reviews have been published recently 8, 9). Although it is well established that TLRs are key innate immune sensors, the recent discovery of novel PRR family members that are able to activate NF-κB or IFN-β suggests that some TLR-elicited responses might be redundant with similar signaling cascades triggered by other PRRs 10, 11, 12. Interestingly, this hypothesis is supported by the unexpected observation that patients devoid of functional IRAK4, an important kinase for TLR signaling, show a relatively mild disease phenotype because they have a limited and transient susceptibility to infection by only a few pyogenic bacteria during childhood [13].

Here, we will review the function and biology of a family of recently identified intracellular PRRs, namely the NACHT [domain present in neuronal apoptosis inhibitory protein (NAIP), CIITA, HET-E and TP1]-LRRs (NLRs), whose emerging function is to detect intracellular pathogens or danger signals in general (Table 1). In particular, we focus on recent insights gained into the emerging roles of nucleotide-binding oligomerization domains (NODs) and NALP3 [NACHT-, LRR- and pyrin domain (PYD)-containing protein 3] in inflammation. For more general reviews on NLRs, we refer to two recently published articles 12, 14.