An inherited mutation in <i>NLRC4</i> causes autoinflammation in human and mice

Kitamura, Akiko; Sasaki, Yuki; Abe, Takaya; Kano, Hiroki; Yasutomo, Koji

doi:10.1084/jem.20141091

Cited by 245 publications

(226 citation statements)

References 31 publications

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“…However, sterile inflammatory conditions involving NLRC4 in other tissues are now emerging in the literature. Autoinflammatory conditions caused by activating mutations in NLRC4 (similar to the CAPS syndromes caused by activating mutations in NLRP3) have been described recently (29)(30)(31). NLRP3 is regarded as the canonical sensor of sterile injury or stress, and so to consider how NLRC4 may sense DAMPs it is sensible to draw comparisons to NLRP3.…”

Section: Discussionmentioning

confidence: 99%

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Dénes

Coutts

Lénárt

et al. 2015

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

222

223

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Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated specklike protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.inflammation | inflammasome | cerebral ischemia | brain injury | cell death

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Section: Discussionmentioning

confidence: 99%

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Dénes

Coutts

Lénárt

et al. 2015

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

222

223

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“…Several inflammasomes respond to a distinctive set of microbial pathogens (5). Activating mutations in the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) member Nlrc4 were recently shown to induce autoinflammation in patients (6)(7)(8). Moreover, the inflammasome assembled by Nlrc4 is critically important for clearing a variety of bacterial infections, including Salmonella enterica serovar Typhimurium (S. Typhimurium), Shigella flexneri, Pseudomonas aeruginosa, Burkholderia thailandensis, and Legionella pneumophila (3,(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5

Matusiak

Opdenbosch

Walle

et al. 2015

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

109

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The Nlrc4 inflammasome contributes to immunity against intracellular pathogens that express flagellin and type III secretion systems, and activating mutations in NLRC4 cause autoinflammation in patients. Both Naip5 and phosphorylation of Nlrc4 at Ser533 are required for flagellin-induced inflammasome activation, but how these events converge upon inflammasome activation is not known. Here, we showed that Nlrc4 phosphorylation occurs independently of Naip5 detection of flagellin because Naip5 deletion in macrophages abolished caspase-1 activation, interleukin (IL)-1β secretion, and pyroptosis, but not Nlrc4 phosphorylation by cytosolic flagellin of Salmonella Typhimurium and Yersinia enterocolitica. ASC speck formation and caspase-1 expression also were dispensable for Nlrc4 phosphorylation. Interestingly, Helicobacter pylori flagellin triggered robust Nlrc4 phosphorylation, but failed to elicit caspase-1 maturation, IL-1β secretion, and pyroptosis, suggesting that it retained Nlrc4 Ser533 phosphorylatingactivity despite escaping Naip5 detection. In agreement, the flagellin D0 domain was required and sufficient for Nlrc4 phosphorylation, whereas deletion of the S. Typhimurium flagellin carboxy-terminus prevented caspase-1 maturation only. Collectively, this work suggests a biphasic activation mechanism for the Nlrc4 inflammasome in which Ser533 phosphorylation prepares Nlrc4 for subsequent activation by the flagellin sensor Naip5.NLRC4 | inflammasome | flagellin | caspase-1 | Salmonella

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“…Later, it was shown syndrome with dermatitis, swollen joints, and splenomegaly. Autoinflammation was increased by exposure to cold, and depended on IL-1β and neutrophil IL-17A [71].…”

Section: Nlrp3 Is Recruited To the Same Complex As Phosphorylation Dementioning

confidence: 97%

“…Recently, three missense mutations in NLRC4 were linked to autoinflammatory syndromes. H443P heterozygous mutation was identified in a Japanese family, whose members experienced occasional cold-induced fever, urticaria, and arthralgia [71]. The H443P NLRC4 mutant was oligomerization-prone in the cell system, and mice carrying this mutation developed autoinflammatory NLRC4 activator remains enigmatic.…”

Section: Mutations In Nlrc4 Cause Autoinflammationmentioning

confidence: 99%

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

Hafner-Bratkovič¹

2017

Inflammasome

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Inflammasomes are intracellular multiprotein platforms for the activation of inflammatory caspases. As components of the innate immune system, they play an important role in the fight against microbes. However, aberrant inflammasome activation has been implicated in auto-inflammatory syndromes. This review focuses on the NLRC4 inflammasome. This is perhaps not the most extensively studied, yet its mechanism of activation is by far the best understood. The NLRC4 inflammasome is activated by several proteins originating from intracellular bacteria, which are first sensed by receptors of the NAIP family. Activated NAIP binds NLRC4, which further recruits dormant NLRC4 molecules in a prion-like oligomerization event. NLRC4 enables a strong amplification of the signal, providing a fast and robust host response. The review also discusses peculiar NLRC4 inflammasome functions in promoting eicosanoid biosynthesis, actin reorganization, and its roles in autoinflammatory syndromes and sterile inflammation. Finally, the first inflammasomeindependent engagement of NLRC4 in suppressing melanoma tumor growth is presented. The emerging roles of NLRC4 in various normal and pathological processes demonstrate that there is still plenty to be learned about the NLRC4 mechanism of activation and downstream functions.

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An inherited mutation in NLRC4 causes autoinflammation in human and mice

Cited by 245 publications

References 31 publications

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

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