Response to IL-1-Receptor Antagonist in a Child with Familial Cold Autoinflammatory Syndrome

2007 ◽  
Vol 24 (1) ◽  
pp. 85-89 ◽  
Author(s):  
Susan M. O'Connell ◽  
Grainne M. O'Regan ◽  
Turlough Bolger ◽  
Hal. M. Hoffman ◽  
Andrew Cant ◽  
...  
2015 ◽  
Vol 57 (4) ◽  
pp. e133-e136 ◽  
Author(s):  
Rebecca Nguyen ◽  
Aaron Robinson ◽  
Katherine Nicholls ◽  
George Varigos ◽  
Con Dolianitis

2019 ◽  
Author(s):  
Akhouri Kishore Raghawan ◽  
Rajashree Ramaswamy ◽  
Vegesna Radha ◽  
Ghanshyam Swarup

AbstractNLRC4 is an innate immune receptor, which upon detection of certain pathogens or internal distress signal, initiates caspase-1 mediated inflammatory response. A gain-of-function mutation, H443P in NLRC4, causes familial cold autoinflammatory syndrome (FCAS) characterized by cold-induced hyperactivation of caspase-1 and inflammation. Here, we show that heat shock cognate protein 70 (HSC70) complexes with NLRC4 and negatively regulates caspase-1 activation by NLRC4-H443P. Compared to NLRC4, the structurally altered NLRC4-H443P shows enhanced interaction with HSC70. Knockdown of HSC70 or inhibition of its ATPase activity enhances caspase-1 activation by NLRC4-H443P. Exposure to subnormal temperature resulted in reduced interaction of NLRC4-H443P with HSC70, and an increase in its ability to form ASC-specks and activate caspase-1. By demonstrating that HSC70 differentially interacts with NLRC4-H443P mutant in a temperature-dependent manner to regulate caspase-1 activation, we provide a mechanism for cold-induced inflammation seen in FCAS patients with NLRC4-H443P mutation.


2021 ◽  
Author(s):  
Tadayoshi Karasawa ◽  
Takanori Komada ◽  
Naoya Yamada ◽  
Emi Aizawa ◽  
Yoshiko Mizushina ◽  
...  

SummaryCryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3, which was originally identified as cryopyrin. Familial cold autoinflammatory syndrome (FCAS), the mildest form of CAPS, is characterized by cold-induced inflammation induced by the overproduction of IL-1β. However, the molecular mechanism of how mutated NLRP3 causes inflammasome activation in CAPS remains unclear. Here, we found that CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function as a scaffold for inflammasome activation. Cold exposure promoted inflammasome assembly and subsequent IL-1β release triggered by mutated NLRP3. While K+ efflux was dispensable, Ca2+ was indispensable for mutated NLRP3-mediated inflammasome assembly. Notably, Ca2+ influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca2+ influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca2+ influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation.


2015 ◽  
Vol 60 (3) ◽  
pp. e1-e1
Author(s):  
R Nguyen ◽  
A Robinson ◽  
K Nicholls ◽  
G Varigos ◽  
C Dolianatis

Author(s):  
Brooke Walterscheid ◽  
Jeannie Nguyen ◽  
Swetha Gadwala ◽  
Goutam Shome ◽  
Michelle Tarbox ◽  
...  

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