REVIEW ARTICLE published: 21 November 2013 doi: 10.3389/fimmu.2013.00393 NOD-like receptors in lung diseases Catherine Chaput, Leif Erik Sander, Norbert Suttorp and Bastian Opitz* Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany Edited by: The lung is a particularly vulnerable organ at the interface of the body and the exterior Thomas A. Kufer, University of environment. It is constantly exposed to microbes and particles by inhalation. The innate Cologne, Germany immune system needs to react promptly and adequately to potential dangers posed by Reviewed by: Dario S. Zamboni, Universidade de these microbes and particles, while at the same time avoiding extensive tissue damage. São Paulo, Brazil Nucleotide-binding oligomerization domain-like receptors (NLRs) represent a group of key Jose A. Bengoechea, Queen’s sensors for microbes and damage in the lung. As such they are important players in various University Belfast, UK infectious as well as acute and chronic sterile inflammatory diseases, such as pneumonia, *Correspondence: chronic obstructive pulmonary disease (COPD), acute lung injury/acute respiratory distress Bastian Opitz, Department of Internal Medicine/Infectious Diseases and syndrome, pneumoconiosis, and asthma. Activation of most known NLRs leads to the pro- Pulmonary Medicine, duction and release of pro-inflammatory cytokines, and/or to the induction of cell death. Charité – Universitätsmedizin Berlin, We will review NLR functions in the lung during infection and sterile inflammation. Augustenburger Platz 1, 13353 Berlin, Germany Keywords: NOD-like receptors, inflammasome, lung, pneumonia, lung injury e-mail: [email protected] INTRODUCTION cell and tissue integrity by so-called pattern-recognition recep- The respiratory tract constitutes a large surface of the body with the tors (PRRs). PRRs comprise different protein families such as the outside environment that is exposed to high volume airflow and transmembrane Toll-like receptors (TLRs) and the intracellularly large numbers of inhaled microbes and particles. The microflora of located nucleotide-binding oligomerization domain (NOD)-like the upper respiratory tract consists of non-pathogenic bacteria but receptors (NLRs) (10–12). PRRs recognize conserved microbial also frequently comprises potential pathogens such as Streptococ- molecules, referred to as pathogen-associated molecular patterns cus pneumoniae and Staphylococcus aureus (1). The distal bronchi (PAMPs) (13). However, recent evidence suggests that recogni- and the alveoli have long been considered sterile, however more tion of disturbed host cell integrity and danger signals might recently microbes that are either aspirated from the upper respira- also play a role in the immune responses to invading pathogens tory tract (2) or constantly reside in the lower airways (3, 4) have (see below). In contrast to the original paradigm (13) it is now been found by culture-independent approaches. well-accepted that PRRs also sense non-microbial ligands gener- Inflammatory disorders of the respiratory tract involving the ated during sterile tissue damage, often called damage-associated innate immune system include both infectious and non-infectious molecular patterns (DAMPs) (14, 15). Moreover, some PRRs can diseases. Lower respiratory tract infections, or pneumonia, gener- additionally respond to large particles and therefore appear to be ally develop when facultative pathogenic microbes that colonize key mediators in pneumoconiosis (16–18). the upper respiratory tract are aspirated or airborne pathogens The NLR family comprises 22 members in humans and even are inhaled. The World Health Organization (WHO) estimates more in mice. Most NLRs share common structural character- 429 million cases of acute lower respiratory tract infections in istics including a C-terminal leucine-rich repeat (LRR) domain, 2004, making it the third leading cause of death world-wide (5). often involved in ligand recognition, a central NOD, and a vari- Moreover, non-infectious and chronic lung diseases substantially able N-terminal effector domain (10). Based on the type of effector contribute to morbidity. Chronic obstructive pulmonary disease domains that is either a caspase recruitment domain (CARD), a (COPD) is mainly caused by tobacco smoke and can exacerbate pyrin domain (PYD), or a baculoviral inhibitor of apoptosis pro- during acute infections, ranks as the number four leading cause of tein repeat (BIR) domain, the NLR family can be further divides death in most industrialized countries (5). Acute lung injury (ALI) into five subfamilies. The NLRA subfamily consist of only one and its severest form, called acute respiratory distress syndrome member, the transcription factor CIITA, of which at least one (ARDS), can develop after infectious as well as non-infectious splice variant expresses a CARD (Figure 1). CIITA is involved insults (6). Another potentially life-threatening disorder is allergic in transcriptional activation of genes encoding major histocom- asthma, which is characterized by airway hyperresponsiveness due patibility complex class II [for detailed discussion of this unique to allergen-triggered airway inflammation causing chronic recur- NLR protein we refer to Ref. (19)]. The NLRB group of NLRs rent airflow obstruction. Long-term exposure to silica, asbestos, or expresses a BIR domain and consists of NAIP1–7 in mice and NAIP coal particles can cause chronic occupational lung disease called in humans. The NLRC subfamily includes the CARD-containing pneumoconiosis. molecules NOD1, NOD2, and NLRC3–5, whereas the 14 known The innate immune system is a key player in various infectious NLRP proteins (NLRP1–14) express a PYD. NLRX1 is the only and non-infectious disorders of the lung (7–9). It senses infec- member of the NLRX subgroup, and the only NLR protein that is tions, sterile tissue damage, and probably any disturbance of host localized in mitochondria (10, 20). Whereas some NLR proteins www.frontiersin.org November 2013 | Volume 4 | Article 393 | 1 Chaput et al. NOD-like receptors in lung diseases FIGURE 1 | Summary of the main characteristics of the NLRs. h and m symbolized a characteristic specific to human or mouse. For more details, refer to the main text. function as bona fide PRRs, other family members act as adaptor predominantly in Gram-negative bacteria (33, 34). NOD2 rec- molecules or regulators of signal transduction. ognizes the muramyl-dipeptide (MDP) MurNAc-l-Ala-d-isoGln, In this review article we discuss the current knowledge about which is conserved in peptidoglycans of the majority of bacteria NLR expression and function in the lung in different pulmonary (35, 36). Other peptidoglycan motifs can be recognized by NOD1 diseases. We have grouped the NLRs based on functional similar- and NOD2, for details refer to review (37). ities and summarize major pathways and common principles of Ligand recognition by both receptors leads to signal transduc- function. tion through Rip2 kinase with downstream activation of MAP kinases and the transcription factor NF-kB, leading to activation NOD1 AND NOD2 of genes encoding different cytokines, chemokines (e.g., IL-8), NOD1 and NOD2 were the first NLR proteins to be discovered and antimicrobial peptides. Both NOD signaling cascades are (21–25). In the lung, NOD1 is expressed in various cell types regulated by small GTPases such as Rac1, however conflicting evi- including lung epithelial cells, endothelial cells, human airway dence exists as to whether this regulation enhances or reduces smooth muscle cells, and different types of leukocytes (26–29). NOD-dependent NF-kB activation (38–40). A recent study sug- NOD2 has been found in alveolar macrophages, neutrophils, and gested that Rac1 is activated upstream of NOD1, and that NOD1 bronchial epithelial cells (30–32). NOD1 responds to bacterial cell essentially senses GTPase activation rather than the peptidoglycan wall peptidoglycan containing meso-diaminopimelic acid found fragments directly (41). NOD1 and NOD2 can recruit the GTPase Frontiers in Immunology | Molecular Innate Immunity November 2013 | Volume 4 | Article 393| 2 Chaput et al. NOD-like receptors in lung diseases ATG16L1 and subsequently stimulate autophagy, a highly con- NOD2-activating potential compared to the MDP (53). NOD2 served bulk degradation system with antimicrobial activity against controls inflammatory responses to S. aureus pneumonia (49), intracellular pathogens (42). and it is also required to clear pneumococcal colonization of the Among the studied lung pathogens, NOD1 responds to upper respiratory tract by CCR2-dependently recruited mono- Chlamydophila pneumoniae, Legionella pneumophila, Klebsiella cytes/macrophages. It was shown that professional phagocytes pneumoniae, Haemophilus influenzae, and Pseudomonas aerug- produce CCL2 after LysM-mediated bacterial digestion and subse- inosa (32, 40, 43–47), whereas NOD2 senses S. pneumoniae, quent NOD2-dependent detection of S. pneumoniae-derived pep- S. aureus, Escherichia coli, C. pneumoniae, and Mycobacterium tidoglycan (48). Similarly, NOD1 controls neutrophil-dependent −/− tuberculosis (30–32, 44, 48–50)(Figure 2). Accordingly, Rip2 clearance of nasopharyngeal colonization with encapsulated H. −/− −/− mice – and to a lesser extend also Nod1 and Nod2 mice – influenzae in mice, whereas it is redundant for non-encapsulated display impaired chemokine production, neutrophil recruitment, strains (46). NOD1 might critically