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1.
Cell Rep ; 30(8): 2501-2511.e5, 2020 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-32101731

RESUMEN

Pro-inflammatory caspase-1 is a key player in innate immunity. Caspase-1 processes interleukin (IL)-1ß and IL-18 to their mature forms and triggers pyroptosis. These caspase-1 functions are linked to its enzymatic activity. However, loss-of-function missense mutations in CASP1 do not prevent autoinflammation in patients, despite decreased IL-1ß production. In vitro data suggest that enzymatically inactive caspase-1 drives inflammation via enhanced nuclear factor κB (NF-κB) activation, independent of IL-1ß processing. Here, we report two mouse models of enzymatically inactive caspase-1-C284A, demonstrating the relevance of this pathway in vivo. In contrast to Casp1-/- mice, caspase-1-C284A mice show pronounced hypothermia and increased levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and IL-6 when challenged with lipopolysaccharide (LPS). Caspase-1-C284A signaling is RIP2 dependent and mediated by TNF-α but independent of the NLRP3 inflammasome. LPS-stimulated whole blood from patients carrying loss-of-function missense mutations in CASP1 secretes higher amounts of TNF-α. Taken together, these results reveal non-canonical caspase-1 signaling in vivo.


Asunto(s)
Caspasa 1/metabolismo , Inflamación/patología , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Adolescente , Adulto , Animales , Niño , Preescolar , Sitios Genéticos , Genotipo , Células HEK293 , Heterocigoto , Humanos , Ratones Endogámicos C57BL , Mutación/genética , Adulto Joven
2.
Oncoimmunology ; 2(12): e26770, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-24498554

RESUMEN

We have recently described a novel modular targeting platform for T cell recruitment that not only efficiently replaces but also is superior to conventional T cell-engaging bispecific antibodies as it allows for the flexible targeting of several antigens and the delivery of co-stimulatory ligands to malignant lesions, thereby enhancing the antitumor potential of redirected T cells.

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