Very Early-Onset IBD-Associated IL-18opathy Treated with an Anti-IL-18 Antibody.

: The aetiology of inflammatory bowel disease (IBD), particularly if occurring early in childhood, is a diverse and patient-focused treatment that is required when standard therapy is ineffective. A clinical case report is presented of a child with very early-onset IBD (VEOIBD) and evidence of high serum IL-18 responding to anti-IL-18 immunotherapy. Detailed cytokine profiling was performed by ELISA and multiplex assay flow cytometry.

Proximity labelling of pro-interleukin-1α reveals evolutionary conserved nuclear interactions.

Interleukin-1α is a suggested dual-function cytokine that diverged from interleukin-1β in mammals potentially by acquiring additional biological roles that relate to highly conserved regions in the pro-domain of interleukin-1α, including a nuclear localisation sequence and histone acetyltransferase-binding domains. Why evolution modified pro-interleukin-1α's subcellular location and protein interactome, and how this shaped interleukin-1α's intracellular role, is unknown. Here we show that TurboID proximity labelling with pro-interleukin-1α suggests a nuclear role for pro-interleukin-1α that involves interaction with histone acetyltransferases, including EP300.

Pyroptosis leads to loss of centrosomal integrity in macrophages.

NLRP3 forms a multiprotein inflammasome complex to initiate the inflammatory response when macrophages sense infection or tissue damage, which leads to caspase-1 activation, maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and Gasdermin-D (GSDMD) mediated pyroptosis. NLRP3 inflammasome activity must be controlled as unregulated and chronic inflammation underlies inflammatory and autoimmune diseases. Several findings uncovered that NLRP3 inflammasome activity is under the regulation of centrosome localized proteins such as NEK7 and HDAC6, however, whether the centrosome composition or structure is altered during the inflammasome activation is not known.

Type I interferon regulates interleukin-1beta and IL-18 production and secretion in human macrophages.

Inflammasomes are immune complexes whose activation leads to the release of pro-inflammatory cytokines IL-18 and IL-1β. Type I IFNs play a role in fighting infection and stimulate the expression of IFN-stimulated genes (ISGs) involved in inflammation. Despite the importance of these cytokines in inflammation, the regulation of inflammasomes by type I IFNs remains poorly understood.

Method to Measure Ubiquitination of NLRs.

Posttranslational modifications are crucial in determining the functions of proteins in the cell. Modification of the NLRP3 inflammasome by the ubiquitin system has recently emerged as a new level of regulation of the inflammasome complex. Here we describe a method to detect poly-ubiquitination of NRLP3 using two different approaches: (i) detection with a ubiquitin antibody or (ii) using TUBEs (Tandem Ubiquitin Binding entities).