Publications

Parkinson's disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein-rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein-mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for PD.

PKCε has been shown to play a key role in the effect of the Gram-negative bacterial product LPS; however, the target for PKCε in LPS signaling is unknown. LPS signaling is mediated by Toll-like receptor 4, which uses four adapter proteins, MyD88, MyD88 adapter-like (Mal), Toll/IL-1R domain-containing adapter inducing IFN-β (Trif), and Trif-related adapter molecule (TRAM). Here we show that TRAM is transiently phosphorylated by PKCε on serine-16 in an LPS-dependent manner. Activation of IFN regulatory factor 3 and induction of the chemokine RANTES, which are both TRAM-dependent, were attenuated in PKCε-deficient cells. TRAMS16A is inactive when overexpressed and is attenuated in its ability to reconstitute signaling in TRAM-deficient cells. We have therefore uncovered a key process in Toll-like receptor 4 signaling, identifying TRAM as the target for PKCε.

Conference Article| February 01 1995 Autocrine regulation of the transcription factor NFκB by TNFα in the human T cell lymphoma line Hut 78 Roisin Cleere; Roisin Cleere 1Department of Biochemistry, Trinity College Dublin, Ireland Search for other works by this author on: This Site PubMed Google Scholar Aideen Long; Aideen Long *Department of Clinical Medicine, Trinity College Dublin, Ireland Search for other works by this author on: This Site PubMed Google Scholar Dermot Kelleher; Dermot Kelleher *Department of Clinical Medicine, Trinity College Dublin, Ireland Search for other works by this author on: This Site PubMed Google Scholar Luke A.J. O'Neill Luke A.J. O'Neill 1Department of Biochemistry, Trinity College Dublin, Ireland Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1995) 23 (1): 113S. https://doi.org/10.1042/bst023113s Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Roisin Cleere, Aideen Long, Dermot Kelleher, Luke A.J. O'Neill; Autocrine regulation of the transcription factor NFκB by TNFα in the human T cell lymphoma line Hut 78. Biochem Soc Trans 1 February 1995; 23 (1): 113S. doi: https://doi.org/10.1042/bst023113s Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: IL1, interleukin 1, TNFα, tumour necrosis factor α, PMA, phorbol myristate acetate, TPCK, Tosylphenylalanyl-chloromethylketone This content is only available as a PDF. © 1995 Biochemical Society1995 Article PDF first page preview Close Modal You do not currently have access to this content.

Analysis of the human genome sequence and other DNA databases is proceeding at a rapid pace, and immunologists are playing an important role in the effort to ascribe functions to putative gene products. An excellent, recent example is the description of six gene sequences predicted to encode homologs of interleukin-1 (IL-1), named IL-1F5–IL-1F10. Indications of a possible role for these homologs in immunity and inflammation are starting to emerge. Most are expressed in monocytes, macrophages and/or dendritic cells; IL-1F5 and IL-1F9 are expressed strongly in keratinocytes; and the expression of IL-1F9 is induced in skin during contact hypersensitivity and in psoriasis patients. IL-1F7 and IL-1F10 bind to the soluble type I IL-1 receptor (IL-1RI) and IL-18R, respectively. Specific functions for these proteins are currently being sought.

Severe coronavirus disease 2019 (COVID-19) is characterized by respiratory failure, shock or multiorgan dysfunction, often accompanied by systemic hyperinflammation and dysregulated cytokine release. These features are linked to the intense and rapid stimulation of the innate immune response. The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a central player in inflammatory macrophage activation which via caspase-1 activation leads to the release of the mature forms of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and via cleavage of Gasdermin D pyroptosis, an inflammatory form of cell death. Here, we discuss the role of NLRP3 activation in COVID-19 and clinical trials currently underway to target NLRP3 to treat severe COVID-19.