Differential Requirements for NAIP5 in Activation of the NLRC4 Inflammasome

Lightfield, Karla L.; Persson, Jenny; Trinidad, Norver J.; Brubaker, Sky W.; Kofoed, Eric M.; Sauer, John-Demian; Dunipace, Eric A.; Warren, Sarah; Miao, Edward A.; Vance, Russell E.

doi:10.1128/iai.01187-10

Cited by 121 publications

(109 citation statements)

References 30 publications

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“…These data demonstrated that L94 was a critical residue for the engagement of the inflammasome via IPAF, in addition to residues present at the C terminus of the D0 domain of flagellin monomer (14,17,19). Alternatively, other Nod-like receptors such as Naip5 (19,20) may also be involved in the differential binding of flagellin L94.…”

Section: Discussionmentioning

confidence: 96%

Toll-like receptor 5 (TLR5), IL-1β secretion, and asparagine endopeptidase are critical factors for alveolar macrophage phagocytosis and bacterial killing

Descamps

Gars

Balloy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A deficit in early clearance of Pseudomonas aeruginosa (P. aeruginosa) is crucial in nosocomial pneumonia and in chronic lung infections. Few studies have addressed the role of Toll-like receptors (TLRs), which are early pathogen associated molecular pattern receptors, in pathogen uptake and clearance by alveolar macrophages (AMs). Here, we report that TLR5 engagement is crucial for bacterial clearance by AMs in vitro and in vivo because unflagellated P. aeruginosa or different mutants defective in TLR5 activation were resistant to AM phagocytosis and killing. In addition, the clearance of PAK (a wild-type P. aeruginosa strain) by primary AMs was causally associated with increased IL-1β release, which was dramatically reduced with PAK mutants or in WT PAK-infected primary TLR5−/− AMs, demonstrating the dependence of IL-1β production on TLR5. We showed that this IL-1β production was important in endosomal pH acidification and in inducing the killing of bacteria by AMs through asparagine endopeptidase (AEP), a key endosomal cysteine protease. In agreement, AMs from IL-1R1 −/− and AEP −/− mice were unable to kill P. aeruginosa. Altogether, these findings demonstrate that TLR5 engagement plays a major role in P. aeruginosa internalization and in triggering IL-1β formation.flagellin | interleukin-1 | lysosomal protease T he opportunist Gram-negative bacterium, Pseudomonas aeruginosa, is particularly important in nosocomial pneumonia and in chronic lung diseases such as cystic fibrosis (1). Alveolar macrophages (AMs) lie at the forefront of lung defense against pathogens such as P. aeruginosa. The main function of AMs is to clear pathogens (2), and a deficiency in early recognition of P. aeruginosa by AMs has been suspected in these pathologies (3,4). Research has shown that pathogen-associated molecular patterns (PAMPs) are recognized by specific Toll-like receptors (TLRs) at the surface of phagocytes and mucosal epithelial cells. Surprisingly, although numerous studies have associated the ligand-induced TLR engagement to cytokine and chemokine production from phagocytes (5, 6), comparatively fewer studies have investigated the importance of TLRs in pathogen phagocytosis and killing. Furthermore, these studies have mostly used macrophages from bone marrow-differentiated cells (BMDMs), few have used live bacteria, and even fewer have used flagellated bacteria such as P. aeruginosa. Moreover most studies have used primed phagocytes (with LPS, zymosan) to boost pathogen uptake. Despite these caveats, the recruitment of membrane TLRs to phagosomes upon phagocytosis has been demonstrated (7-10), except for TLR5. TLR2, TLR4, and the adaptor molecule MyD88 have been shown to be important molecules in processing of heat-killed Escherichia coli and Staphylococcus aureus by BMDMs in late endosomes and lysosomes (9-11), suggesting that a blockade in phagosome maturation was occurring in phagocytes deleted for these molecules.TLR5 is thought to be one of the key receptors implicated in the recognition of P. aeruginosa (5, 8), bu...

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Section: Discussionmentioning

confidence: 96%

Toll-like receptor 5 (TLR5), IL-1β secretion, and asparagine endopeptidase are critical factors for alveolar macrophage phagocytosis and bacterial killing

Descamps

Gars

Balloy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Consistent with a role for IL-1 in the in vivo differentiation of Th17 cells during L. pneumophila infection, our results show compromised Th17 differentiation in the absence of MyD88, caspase-1, IL-1, and, to some extent, IPAF, indicating an important role for inflammasome activation and the subsequent secretion of IL-1 in the promotion of Th17 responses. L. pneumophila-derived flagellin was shown to activate cell surface TLR5 (46); however, it can also access the cytosol via L. pneumophila T4SS, where it activates the NLRs IPAF and Naip5 (35)(36)(37)47). Because both cytosolic PRRs were shown to activate caspase-1 and, thereby, induce the secretion of IL-1b (37,48), this likely explains the fact that Th17 responses were less impaired in the sole absence of IPAF compared with the absence of MyD88, caspase-1, or IL-1R.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies on the innate immune response to L. pneumophila demonstrated that inflammasome activation via recognition of L. pneumophila-derived flagellin plays a critical role in the secretion of IL-1b (35)(36)(37). It is well established that IL-1 has a strong influence on CD4 T cell differentiation, mainly toward the Th17 lineage (38-41).…”

Section: Il-1 and The Ipaf Inflammasome Promote Th17 Development In Vivomentioning

confidence: 99%

Innate Instruction of CD4+ T Cell Immunity in Respiratory Bacterial Infection

Trunk

Oxenius

2012

The Journal of Immunology

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The innate immune system recognizes invading microbes via conserved pattern recognition receptors and uses inflammatory signals to concert adaptive defense mechanisms. However, microbial and host parameters involved in CD4 T cell priming and direction of Th1, Th2, and Th17 differentiation in the context of infections with complex pathogens in vivo are incompletely understood. In this study, we used Legionella pneumophila, which triggers membrane-bound and cytosolic pattern recognition receptors, to study the innate instruction of adaptive immunity. Upon airway infection, T cells were primed exclusively in the lung-draining lymph nodes and differentiated into Th1/Th17 effector cells upon arrival in the lung. Although engagement of membrane-bound pattern recognition receptors was sufficient for initial T cell activation and proliferation, cytosolic pattern recognition was required for effector T cell differentiation. In the absence of cytoplasmic pattern recognition, MyD88 was key for T cell priming, whereas, in its presence, MyD88-mediated signals were crucial for Th17 differentiation. Specifically, cytosolic sensing of Legionella-derived flagellin, inflammasome activation, and IL-1 signaling contributed to Th17 development. In the absence of TLR signaling, a simultaneous Th1/Th2 response developed that was independent of the inflammasome–IL-1 axis. Collectively, these data illustrate the important role for various pattern recognition receptors triggered by complex pathogens and how they each instruct specific differentiation programs in responding CD4 T cells.

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“…In its monomeric form it is recognized by two Pathogen Recognition Receptors (PRRs), TLR5 that senses extracellular FliC 16 and NLRC4/NAIP5 inflammasome that detects intracellular flagellin 17,18 . When FliC is sensed by the PRRs an important inflammatory response is triggered.…”

Section: Introductionmentioning

confidence: 99%