NOD-Like Receptors: Versatile Cytosolic Sentinels

Motta, Vinı́cius; Soares, Fraser; Sun, Tian; Philpott, Dana J.

doi:10.1152/physrev.00009.2014

Cited by 275 publications

(231 citation statements)

References 298 publications

(362 reference statements)

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“…This has been shown in the context of lung infection of knockout mice and infected BMD macrophages obtained from knockout mice as well as a human epithelial cell line (33,(40)(41)(42)(43). The activation of the MAPK and NF-B pathways is in part dependent upon NOD signaling, which is contingent upon RIP2 (44,45). Thus, in order to assess the impact of NOD signaling on L. pneumophila infection of human macrophages as well as T2S-mediated dampening, we made a stable RIP2 knockdown U937 cell line with a 72% decrease in the protein level, as shown by immunoblotting (Fig.…”

Section: Resultsmentioning

confidence: 90%

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

2017

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Previously, we reported that mutants of Legionella pneumophila lacking a type II secretion (T2S) system elicit higher levels of cytokines (e.g., interleukin-6 [IL-6]) following infection of U937 cells, a human macrophage-like cell line. We now show that this effect of T2S is also manifest upon infection of human THP-1 macrophages and peripheral blood monocytes but does not occur during infection of murine macrophages. Supporting the hypothesis that T2S acts to dampen the triggering of an innate immune response, we observed that the mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa B (NF-B) pathways are more highly stimulated upon infection with the T2S mutant than upon infection with the wild type. By using short hairpin RNA to deplete proteins involved in specific pathogen-associated molecular pattern (PAMP) recognition pathways, we determined that the dampening effect of the T2S system was not dependent on nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible protein I (RIG-I)-like receptors (RLRs), double-stranded RNA (dsRNA)-dependent protein kinase receptor (PKR), or TIR domain-containing adaptor inducing interferon beta (TRIF) signaling or an apoptosis-associated speck-like protein containing a CARD (ASC)-or caspase-4-dependent inflammasome. However, the dampening effect of T2S on IL-6 production was significantly reduced upon gene knockdown of myeloid differentiation primary response 88 (MyD88), TANK binding kinase 1 (TBK1), or Toll-like receptor 2 (TLR2). These data indicate that the L. pneumophila T2S system dampens the signaling of the TLR2 pathway in infected human macrophages. We also document the importance of PKR, TRIF, and TBK1 in cytokine secretion during L. pneumophila infection of macrophages.KEYWORDS Legionella pneumophila, TLR2, cytokine, innate immunity, macrophage, type II secretion L egionella pneumophila, a Gram-negative bacterium that is widespread in aquatic habitats, is the principal agent of Legionnaires' disease pneumonia (1-6). In the lungs, Legionella bacteria invade and grow in resident macrophages and then trigger severe inflammation (2). In macrophages, L. pneumophila evades the degradative lysosomal pathway and replicates to large numbers within a membrane-bound vacuole, the Legionella-containing vacuole (LCV) (7,8). Two protein secretion systems, Lsp type II secretion (T2S) and Dot/Icm type IV secretion (T4S), play major roles in the pathogenesis of L. pneumophila (9, 10). In T2S, protein substrates are first translocated across the inner membrane, and upon the action of the T2S pilus-like apparatus, they then exit the bacterial cell through a specific outer membrane pore (11). Using proteomics and enzymatic assays, we have shown that the T2S system of L. pneumo-

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Section: Resultsmentioning

confidence: 90%

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

2017

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“…Several inflammasomes have been identified, and all but one (that formed by AIM2) contain proteins that are part of the nucleotidebinding domain leucine-rich repeat (NLR) family. These NLRs serve as cytosolic PRRs and are activated upon recognition of cytosolic PAMPs or danger signals (2,11,15). For some NLRs, such as NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) mediates inflammasome assembly by interacting with capase-1 and the NLR (11,13,15).…”

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confidence: 99%

“…eing the first line of defense against invading pathogens, the innate immune system has evolved to respond to general patterns of infection, termed pathogen-associated molecular patterns (PAMPs), via pattern recognition receptors (PRRs) (1,2). Tolllike receptors (TLRs), acting as PRRs, detect distinct PAMPs from invading bacteria, such as flagellin (TLR5) and lipopolysaccharide (LPS; TLR4).…”

mentioning

confidence: 99%

“…Complexes of NLRs and ASC form large structures in macrophages that can be detected as foci by microscopic techniques (17)(18)(19). In cases where inflammasome assembly is triggered in a T3SS-dependent manner upon infection of macrophages with pathogens, specific PAMPs identified to activate caspase-1 upon contaminating the cytosol include ectopically translocated flagellin, rod proteins, needle proteins, and translocated effector proteins (2,(11)(12)(13)15). The NLRP3 inflammasome requires an initial priming signal (also referred to as signal 1), which can be achieved through TLR signaling, and induces expression of NLRP3 and pro-IL-1␤ via the MAPK and NF-B pathways (2,11,15).…”

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confidence: 99%

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Uncovering an Important Role for YopJ in the Inhibition of Caspase-1 in Activated Macrophages and Promoting Yersinia pseudotuberculosis Virulence

et al. 2016

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Being the first line of defense against invading pathogens, the innate immune system has evolved to respond to general patterns of infection, termed pathogen-associated molecular patterns (PAMPs), via pattern recognition receptors (PRRs) (1, 2). Tolllike receptors (TLRs), acting as PRRs, detect distinct PAMPs from invading bacteria, such as flagellin (TLR5) and lipopolysaccharide (LPS; TLR4). Upon PAMP recognition, TLRs activate mitogenactivated protein kinase (MAPK) and nuclear factor-B (NF-B) pathways, which direct production of host-protective factors such as proinflammatory cytokines (3, 4). Bacterial pathogens produce virulence factors that inhibit PRR-directed innate immune responses in order to promote infection (5, 6). For example, numerous Gram-negative bacterial pathogens encode type III secretion systems (T3SSs) that are used to counteract host innate immune responses (7). During bacterium-host cell contact, T3SSs are activated and translocate effectors across the plasma membrane and into the eukaryotic cytosol. Translocated effectors inhibit innate immune responses and promote pathogenesis (7,8). In order to counteract infection by virulent pathogens, host cells can sense perturbations caused by T3SSs and/or effectors and produce heightened innate immune responses (9, 10).Disruptions induced by T3SSs and/or effectors in macrophages infected with bacterial pathogens commonly result in the activation of caspase-1 (11-14). Active caspase-1 promotes maturation and secretion of cytokines such as interleukin-1␤ (IL-1␤) and IL-18, which are produced as inactive precursors. Caspase-1 is also produced as a proenzyme, and its activation typically occurs in an inflammasome, a multioligomeric complex that serves as a molecular platform for the recruitment and auto-proteolytic cleavage of procaspase-1 (11-13, 15). Active caspase-1 also induces lysosome exocytosis and a form of inflammatory cell death, termed pyroptosis, which is characterized by osmotic swelling of the macrophage and subsequent rupture of the plasma membrane, resulting in the release of proinflammatory molecules (16). Several inflammasomes have been identified, and all but one (that formed by AIM2) contain proteins that are part of the nucleotidebinding domain leucine-rich repeat (NLR) family. These NLRs serve as cytosolic PRRs and are activated upon recognition of cytosolic PAMPs or danger signals (2,11,15). For some NLRs, such as NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) mediates inflammasome assembly by interacting with capase-1 and the NLR (11,13,15). Complexes of NLRs and ASC form large structures in macrophages that can be detected as foci by microscopic techniques (17)(18)(19). In cases where inflammasome assembly is

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“…NLRs are a large family of cytoplasmic receptors that recognise both microbial ligands and DAMPs and are coupled to inflammasome activation and inflammatory signalling pathways [31]. NOD1 and NOD2 are members of the NLRC subfamily that induce inflammatory signalling via kinase and caspase activation.…”

Section: Damp Receptors and Cardiac Remodellingmentioning

confidence: 99%

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

Turner

2016

Journal of Molecular and Cellular Cardiology

168

124

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Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

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NOD-Like Receptors: Versatile Cytosolic Sentinels

Cited by 275 publications

References 298 publications

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

Uncovering an Important Role for YopJ in the Inhibition of Caspase-1 in Activated Macrophages and Promoting Yersinia pseudotuberculosis Virulence

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

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