The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation.

Current Biology (Impact Factor: 9.49). 03/2001; 11(4):R118-20. DOI: 10.1016/S0960-9822(01)00056-2
Source: PubMed
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    ABSTRACT: Hemorrhagic shock (HS) promotes the development of systemic inflammatory response syndrome and organ injury by activating and priming the innate immune system for an exaggerated inflammatory response through, as of yet, unclear mechanisms. IL-1β also plays an important role in the development of post-HS systemic inflammatory response syndrome and active IL-1β production is tightly controlled by the inflammasome. Pyrin, a protein of 781 aa with pyrin domain at the N-terminal, negatively regulates inflammasome activation through interaction with nucleotide-binding oligomerization domain-like receptor protein (NLRP). Expression of pyrin can be induced by LPS and cytokines, and IL-10 is a known potent inducer of pyrin expression in macrophages. In the current study, we tested the hypothesis that HS downregulates IL-10 and therefore decreases pyrin expression to promote inflammasome activation and subsequent IL-1β processing and secretion in the lungs. Our results show that LPS, while activating Nlrp3 inflammasome in the lungs, also induced pyrin expression, which in turn suppressed inflammasome activation. More importantly, LPS-mediated upregulation of IL-10 enhanced pyrin expression, which serves, particularly in later phases, as a potent negative-feedback mechanism regulating inflammasome activation. However, HS-mediated suppression of IL-10 expression in alveolar macrophages attenuated the upregulation of pyrin in alveolar macrophages and lung endothelial cells and thereby significantly enhanced inflammasome activation and IL-1β secretion in the lungs. This study demonstrates a novel mechanism by which HS suppresses negative-feedback regulation of Nlrp3 inflammasome to enhance IL-1β secretion in response to subsequent LPS challenge and so primes for inflammation.
    The Journal of Immunology 04/2013; · 5.52 Impact Factor
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    ABSTRACT: Familial Mediterranean fever (FMF) is a recessive, autosomal, auto-inflammatory disorder characterised by brief, recurring, self-limited episodes of fever and serositis resulting in abdominal, chest, joint and muscular pain; it is the most common of the periodic hereditary fevers and mostly affects Mediterranean populations. Daily administration of colchicine, a tricyclic alkaloid with anti-microtubule and anti-inflammatory properties, prevents the recurrence of FMF attacks and the development of secondary (AA) amyloidosis, the major long-tem complication of FMF. Colchicine is generally safe and well-tolerated; nevertheless, 5-10 % of FMF patients do not respond to conventional treatment, while another 2-5 % of patients are colchicine-intolerant because of toxicity issues, leading physicians to search for alternative therapeutic strategies. Recent new insights into the mechanisms of auto-inflammation add further proof to the efficacy of IL-1 targeting drugs in colchicine non-responder/intolerant FMF patients. A systematic study of relevant literature through PubMed/Medline was performed in order to identify publications reporting IL-1β biological treatment of FMF. Treatment methods, comorbidities, clinical response and side effects in literature case reports were analysed, as well as recent advances in the pathogenesis of auto-inflammation mechanisms in FMF and the causes of colchicine resistance or toxicity in common clinical practice. The paradigmatic experience of an FMF patient with severe FMF mutations (M694V/M694V) suffering from colchicine toxicity and successfully treated with anakinra is also reported. The present data show that anti-IL-1β biological treatment is actually a therapeutic option for FMF patients unresponsive or intolerant to colchicine or in FMF patients with concomitant vasculitis.
    Clinical Reviews in Allergy & Immunology 01/2013; · 5.59 Impact Factor
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    ABSTRACT: AIM2 is a cytosolic dsDNA sensor essential for innate immune responses against DNA viruses and bacteria such as Francisella and Listeria. Upon dsDNA engagement, the AIM2 amino terminal pyrin domain (PYD) is responsible for downstream signaling to the adapter protein ASC through homotypic PYD:PYD interactions and the assembly of an inflammasome. Towards a better understanding of the AIM2 signaling mechanism, we determined the crystal structure of the human AIM2 PYD. The structure reveals a death domain fold, with a short α3 helix that is buttressed by a highly conserved lysine residue at the α2 helix, which may stabilize the α3 helix for potential interaction with partner domains. The surface of the AIM2 PYD exhibits distinct charge distribution, with highly acidic α1-α2 helices and highly basic α5-α6 helices. A prominent solvent-exposed hydrophobic patch formed by residues F27 and F28 at the α2 helix resembles a similar surface involved in the death effector domain homotypic interactions. Docking studies suggest that the AIM2 PYD may bind the AIM2 HIN domain or ASC PYD using overlapping surface near the α2 helix. This may ensure that AIM2 interacts with the downstream adapter ASC only upon release of the autoinhibition by the dsDNA ligand. Our work thus unveils novel structural features of the AIM2 PYD, and provides insights into the potential mechanisms of the PYD:HIN and PYD:PYD interactions important for the AIM2 autoinhibition and inflammasome assembly.
    Journal of Biological Chemistry 03/2013; · 4.65 Impact Factor