The NLRP3 inflammasome is a multiprotein complex regulating the secretion of IL-1? and IL-18 in response to a variety of stimuli, including pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Upon activation, the apoptosis associated speck-like protein (ASC) adaptor recruits caspase-1 to the NLRP3 inflammasome complex, where it first undergoes auto-cleavage and then processes the inactive precursors of IL-1? and IL-18. Importantly, NLRP3 is not responsive to stimulation unless primed by an NF-?B-triggering signal, such as LPS. Recent studies have identified an alternative mechanism leading to caspase-1 activation in mouse. This “non-canonical” pathway requires the inflammatory caspase-11 participating to the regulation of IL-1?, in addition to IL-1? and IL-18. It was also reported that Gram-negative bacteria, but not Gram-positive bacteria, or intracellular LPS are the main triggers of the non-canonical pathway. In vivo evidences indicate that, the non-canonical pathway seems detrimental in murine models of sepsis. However, the existence and the relevance of the non-canonical inflammasome in humans have not been demonstrated yet. Thus, we investigated whether the inflammatory caspase-4 and caspase-5 - human homologs of murine caspase-11- are induced in human monocytes after TLR4 stimulation by LPS. We found that caspase-5, but not caspase-4, is activated in LPS-treated monocytes. Importantly, the release of IL-1? and IL-1? depends on caspase-5 through a mechanism that requires SYK, PLCg and calcium (Ca2+) flux.
Study of caspase - 5 regulation during inflammasome activation in human monocytes [Tesi di dottorato]
Università degli Studi di Milano-Bicocca, 2014-07-15
TORSELLO, ANTONIO BIAGIO
Settore BIO/12 - - Biochimica Clinica E Biologia Molecolare Clinica
Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD16015879
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