Intracellular pattern-recognition receptors☆

Dostert, Catherine; Meylan, Etienne; Tschopp, Jürg

doi:10.1016/j.addr.2007.12.003

Cited by 41 publications

(34 citation statements)

References 115 publications

(146 reference statements)

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“…The secretion of all these proteins requires caspase-1 activity (11). The protease itself is activated by multimeric innate immune complexes, the inflammasomes (12,13). Although thalidomide did not influence the expression of inflammasome proteins (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…2A). Caspase-1 is activated in recently identified innate immune complexes called inflammasomes (12,13). A reduction of expression of these inflammasome proteins (caspase-1, ASC, NALP-1/3, tripartite motif-16) inhibits activation of caspase-1 and in turn unconventional protein secretion (11,16,19).…”

Section: Thalidomide Inhibits Unconventional Protein Secretion Withoumentioning

confidence: 99%

“…These proteins are involved in inflammation, cytoprotection, apoptosis, and angiogenesis. Originally, caspase-1 was identified as an activator of the proinflammatory cytokines proIL-1␤ and proIL-18, which also lack a signal peptide (12,13). Caspase-1 itself is activated by innate immune complexes, the inflammasomes (12,13).…”

mentioning

confidence: 99%

“…Originally, caspase-1 was identified as an activator of the proinflammatory cytokines proIL-1␤ and proIL-18, which also lack a signal peptide (12,13). Caspase-1 itself is activated by innate immune complexes, the inflammasomes (12,13). Because caspase-1 activity links inflammation with angiogenesis and because both processes are inhibited in vivo by thalidomide, we analyzed whether thalidomide can inhibit caspase-1 activation.…”

mentioning

confidence: 99%

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Thalidomide Inhibits Activation of Caspase-1

Keller

Sollberger

Beer

2009

The Journal of Immunology

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Thalidomide is an efficient anti-inflammatory and anti-angiogenic drug, but its therapeutic use is problematic due to a strong teratogenic activity. Nevertheless, thalidomide was approved for the treatment of inflammatory skin diseases and certain types of cancer, and it is extensively tested for several other indications. Recently, we demonstrated that active caspase-1, whose activation is dependent on inflammasome complexes, is required for unconventional protein secretion of proinflammatory cytokines such as IL-1 and of the proangiogenic fibroblast growth factor 2. In this study, we show that pharmacological doses of thalidomide strongly reduced the secretion of both proteins. Thalidomide-treated cells also released less of other leaderless proteins, which require caspase-1 activity for their secretion. In line with these findings, the drug inhibited activation and activity of caspase-1 in cultured cells but not in vitro. The latter finding suggests that the pharmacological activity is exerted by a metabolite of the drug. The anti-inflammatory activity of thalidomide was also mediated via caspase-1 in mice. These findings represent a novel mechanism by which thalidomide exerts its pharmacological activity and suggest that inhibition of the activity of IL-1 might represent a novel strategy to substitute thalidomide.

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Section: Discussionmentioning

confidence: 99%

Section: Thalidomide Inhibits Unconventional Protein Secretion Withoumentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Thalidomide Inhibits Activation of Caspase-1

Keller

Sollberger

Beer

2009

The Journal of Immunology

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“…In innate immunity, recognition of highly conserved pathogen-associated molecular patterns (PAMPs) by transmembrane host pattern-recognition receptors such as Toll-like receptors (TLRs) and cytoplasmic sensors including nucleotide-oligomerization domain (Nod)-like receptors initiate signaling cascades driving antimicrobial host defense. 1,2 PAMPs like lipopolysaccharide (LPS), a structural component of Gram-negative bacterial cell walls, form a LPS-TLR complex leading to activation of transcriptional programs including nuclear factor (NF)-B-and Jun/ Fos-targeted expression of inflammatory mediators critical in host defense and stimulation of adaptive immunity, but in excess, detrimental to the host.…”

mentioning

confidence: 99%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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Long-lived monocytes, macrophages, and dendritic cells (DCs) are Toll-like receptor-expressing, antigenpresenting cells derived from a common myeloid lineage that play key roles in innate and adaptive immune responses. Based on immunohistochemical and molecular analyses of inflamed tissues from patients with chronic destructive periodontal disease, these cells, found in the inflammatory infiltrate, may drive the progressive periodontal pathogenesis. To investigate early transcriptional signatures and subsequent proteomic responses to the periodontal pathogen, Porphyromonas gingivalis, donor-matched human blood monocytes, differentiated DCs, and macrophages were exposed to P. gingivalis lipopolysaccharide (LPS) and gene expression levels were measured by oligonucleotide microarrays. In addition to striking differences in constitutive transcriptional profiles between these myeloid populations, we identify a P. gingivalis LPS-inducible convergent, transcriptional core response of more than 400 annotated genes/ESTs among these populations, reflected by a shared, but quantitatively distinct, proteomic response. Nonetheless, clear differences emerged between the monocytes, DCs, and macrophages. The finding that long-lived myeloid inflammatory cells, particularly DCs, rapidly and aggressively respond to P. gingivalis LPS by generating chemokines, proteases, and cytokines capable of driving T-helper cell lineage polarization without evidence of corresponding immunosuppressive pathways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique, and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation.

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Innate instruction of adaptive immunity revisited: the inflammasome

2009

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The innate immune system regulates initial responses to pathogen invasion through a set of conserved pattern recognition receptors (PRR). The best-characterized PRRs are the Toll-like receptors, which regulate not only the initial pathogen defense response, but also adaptive immune responses. Thus, insight into the function of PRRs has major implications for our understanding of the physiology of vaccination and the pathophysiology of human disease. Recent advances in our understanding of a new class of pattern recognition receptors–NOD-like receptors (NLR)–have similarly provided insight into both innate and adaptive immunity. In particular, the NLR Nlrp3 (also known as Nalp3 or Cias1) forms an intracellular multimolecular complex with active caspase-1, called an inflammasome, creating a platform for regulating secretion of interleukin-1 (IL-1) family members. Given the important role of IL-1 in inflammatory diseases, from gout to rheumatoid arthritis, the importance of understanding the regulation of such a cytokine cannot be underestimated. In this review, we address new evidence supporting a role for adaptive immune activation by recently identified NLR agonists, with a particular focus on Nlrp3. Basic questions in our understanding of Nlrp3 inflammasome activation are also presented.

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Intracellular pattern-recognition receptors☆

Cited by 41 publications

References 115 publications

Thalidomide Inhibits Activation of Caspase-1

Thalidomide Inhibits Activation of Caspase-1

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Innate instruction of adaptive immunity revisited: the inflammasome

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