NAIP-NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion with Eicosanoid and IL-18 Release via Activation of Caspase-1 and -8

Rauch, Isabella; Deets, Katherine A.; Ji, Daisy X.; Moltke, Jakob von; Tenthorey, Jeannette; Lee, Angus Y; Philip, Naomi H.; Ayres, Janelle S.; Brodsky, Igor E.; Gronert, Karsten; Vance, Russell E.

doi:10.1016/j.immuni.2017.03.016

Cited by 344 publications

(524 citation statements)

References 51 publications

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“…Nlrp3 −/− , Pycard −/− , Casp11 −/− , Casp1 −/− Casp11 −/− (He et al, 2016), Nlrp6 −/− (Chen et al, 2011), Il18 −/− (Seregin et al, 2017), Aim2 −/− , Il1b −/− (Seo et al, 2015), Casp1 −/− (Man et al, 2017), and Gsdmd −/− mice (Rauch et al, 2017) on C57BL/6 background have been reported. C57BL/6 WT and Ifnar1 −/− (Muller et al, 1994) mice were purchased from Jackson Laboratories.…”

Section: Star Methodsmentioning

confidence: 99%

The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection

Hara

Seregin

Yang

et al. 2018

Cell

212

231

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SUMMARY The activator and composition of the NLRP6 inflammasome remain poorly understood. We find that lipoteichoic acid (LTA), a molecule produced by Gram-positive bacteria, binds and activates NLRP6. In response to cytosolic LTA or infection with Listeria monocytogenes, NLRP6 recruited caspase-11 and caspase-1 via the adaptor ASC. NLRP6 activation by LTA induced processing of caspase-11, which promoted caspase-1 activation and IL-1β/IL-18 maturation in macrophages. Nlrp6−/− and Casp11−/− mice were less susceptible to Listeria monocytogenes infection, which was associated with reduced pathogen loads and impaired IL-18 production. Administration of IL-18 to Nlrp6−/− or Casp11−/− mice restored the susceptibility of mutant mice to Listeria monocytogenes infection. These results reveal a previously unrecognized innate immunity pathway triggered by cytosolic LTA that is sensed by NLRP6 and exacerbates systemic Gram-positive pathogen infection via the production of IL-18.

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Section: Star Methodsmentioning

confidence: 99%

The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection

Hara

Seregin

Yang

et al. 2018

Cell

212

231

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“…Inflammasome activation has also been implicated in expulsion of intestinal epithelial cells (IECs) from the intestinal epithelium prior to pyroptosis in response to microbial infection. While gasdermin D is required for pyroptosis but dispensable for expulsion of IECs[25], the possibility remains that other gasdermins may play a role in IEC expulsion, either alone or with redundancy.…”

Section: Gasdermin D Pores Are the Effectors Of Pyroptosismentioning

confidence: 99%

Gasdermins: Effectors of Pyroptosis

Kovacs

Miao

2017

Trends in Cell Biology

962

662

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Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family.

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“…Recently, a specialized host defense role of the NLRC4 inflammasome was identified in mouse intestinal epithelial cells (IECs). Upon detection of Salmonella within IEC cytoplasm, the NLRC4 inflammasome rapidly forms producing IL-18 and diarrhea-causing eicosanoids (19). Instead of pyroptosis, Salmonella containing IECs undergo IL-18 independent, caspase dependent, non-lytic cell death with subsequent expulsion into the colonic lumen (20).…”

Section: Nlrc4 Inflammasome Biologymentioning

confidence: 99%

“…A growing literature links the intestinal ecosystem with NLRC4 activation and IL-18 production (19,20,28,42). As such, early gut colonization may promote excessive IL-1 family cytokine production in AIFEC patients.…”

Section: Treatment Of Nlrc4 Inflammasomopathiesmentioning

confidence: 99%

NLRC4 inflammasomopathies

Romberg¹,

Vogel

Canna

2017

Current Opinion in Allergy &Amp; Clinical Immunology

107

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Purpose of review The purpose of the review is to highlight developments in autoinflammatory diseases associated with gain-of-function mutations in the gene encoding NLR-family CARD domain-containing protein 4 (NLRC4), the NLRC4-inflammasomopathies. Recent findings Three years since the identification of the first autoinflammation with infantile enterocolitis (AIFEC) patients, there is an improved understanding of how the NLRC4 inflammasome and interleukin 18 (IL-18) contribute to gut inflammation in myeloid and also intestinal epithelial cells. This information has opened new therapeutic avenues to treat AIFEC patients with targeted agents like recombinant IL-18 binding protein and anti-interferon-γ antibodies. Additional phenotypes traditionally associated with NLRP3 mutations like familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), have now also been associated with gain-of-function NLRC4 mutations. Finally, NLRC4 somatic mosaicism has now been identified in a NOMID and an AIFEC patient, a finding emphasizing nontraditional modes of inheritance in autoinflammatory diseases. Summary The NLRC4 inflammasomopathies comprise a growing autoinflammatory disease category that spans a broad clinical spectrum from cold urticaria to NOMID and the often-fatal disease AIFEC. Rapid case identification with biomarkers like elevated serum IL-18 concentrations and early intervention with targeted immunomodulatory therapies are key strategies to improving outcomes for AIFEC patients.

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NAIP-NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion with Eicosanoid and IL-18 Release via Activation of Caspase-1 and -8

Cited by 344 publications

References 51 publications

The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection

The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection

Gasdermins: Effectors of Pyroptosis

NLRC4 inflammasomopathies

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