Publications

2016 Editorial Board

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Preface

M-CSF

No abstract is provided for this article.

Annotating genes with potential roles in the immune system: six new members of the IL-1 family

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.

Preparation of sulfonylureas, especially N-[(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl]benzenesulfonamides, as dual insulin secretagogues and NLRP3 inflammasome inhibitors.

No abstract is provided for this article.

The role of MyD88-like adapters in Toll-like receptor signal transduction

Signal-transduction pathways activated by Toll-like receptors (TLRs) have been the subject of intense investigation because of the key role played by TLRs in the recognition and elimination of microbes. Signalling is initiated by a domain termed the Toll/interleukin-1 (IL-1) receptor (TIR) domain that occurs on the cytosolic face of TLRs. This recruits, via homotypic interactions, adapter proteins that contain TIR domains. Three such adapter proteins have been discovered to date, and have been named MyD88, Mal [MyD88 adapter-like; also known as TIRAP (TIR domain-containing adapter protein)] and Trif (TIR-domain-containing adapter inducing interferon-β). Differences are emerging between TLRs in terms of which adapter is recruited by which TLR. This may lead to specificities in TLR signalling, with pathways being triggered that are specific for the elimination of the invading microbe. However, signals that separate Mal from MyD88 have yet to emerge, although biochemical differences between the two proteins imply that each will have a specific function.

SS4-1 New targets and processes in the control of TLRs and NLRP3

No abstract is provided for this article.

Publisher Correction: Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon

From periphery to center stage: 50 years of advancements in innate immunity

Altered inflammasome activation in neonatal encephalopathy persists in childhood

Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)-1β, IL-1ra and IL-18 are activated by the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)- and NOD-like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme-linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL-1β and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4-7 years were analysed. An increase in serum IL-1ra and IL-18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL-1ra in NE was decreased to normal levels at school age, whereas serum IL-18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school-age NE. NLRP3 and IL-1β gene expression were up-regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up-regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention.

NLRP3, the inflammasome and COVID-19 infection

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.

Fas ligand and silicosis

Silicosis is a lung disease of the industrial age caused by the inhalation of silica. It is still a common and life-threatening occupational disease, particularly in the mining industry. Silicosis starts with inflammation and tissue destruction, followed by tissue repair leading to fibrosis. Pulmonary macrophages ingest the silica, and release a range of inflammatory mediators, most notably TNF. The resulting recruitment of neutrophils promotes the destruction of connective tissue. A recent study by Borges et al. now demonstrates a central role for Fas ligand (FasL) expressed on pulmonary macrophages in the induction of pulmonary silicosis. In a murine model of silicosis, they demonstrate that FasL-deficient mice do not develop the disease. These mice had markedly reduced neutrophil extravasation into bronchoalveolar spaces and decreased production of TNF. The transfer of wild-type macrophages expressing FasL into the mice induced silicosis, and a neutralizing anti-FasL Ab prevented silicosis in wild-type mice. FasL appears to play a role in inducing the apoptosis of macrophages following their ingestion of silica. This might lead to the release of IL-1, IL-18 and neutrophil chemoattractants from the dying macrophages. FasL itself has also been shown to be chemotactic for neutrophils. The study might have relevance for other inflammatory diseases of the lungs and might point the way to new therapies. J. Exp. Med. (2001) 194, 155–163. LON

IL-1

No abstract is provided for this article.

GM-CSF

No abstract is provided for this article.

Immunometabolism and the land of milk and honey

No abstract is provided for this article.

Glucocorticoids Inhibit IRF3 Phosphorylation in Response to Toll-like Receptor-3 and -4 by Targeting TBK1 Activation

Phosphorylation of the transcription factor interferon regulatory factor 3 (IRF3) is essential for the induction of promoters which contain the interferon-stimulated response element (ISRE). IRF3 can be activated by Toll-like receptor 3 (TLR3) in response to the double-stranded RNA mimic poly(I-C) and by TLR4 in response to lipopolysaccharide (LPS). Here we have analyzed the effect of the glucocorticoid dexamethasone on this response. Dexamethasone inhibited the induction of the ISRE-dependent gene RANTES (regulated on activation normal T cell expressed and secreted) in both U373-CD14 cells and human peripheral blood mononuclear cells and also an ISRE luciferase construct, activated by either TLR3 or TLR4. It also inhibited increased phosphorylation of IRF3 in its N terminus in response to LPS and in its C terminus on Ser-396 in response to either poly(I-C) or LPS. Several dexamethasone-induced phosphatases were tested for possible involvement in these effects; MKP1 did not appear to be involved, although MKP2 and MKP5 both partially inhibited induction of the ISRE, pointing to their possible involvement in the effect of dexamethasone. Importantly, we found that dexamethasone could inhibit TBK1 kinase activity and TBK1 phosphorylation on Ser-172, both of which are required for IRF3 phosphorylation downstream of TLR3 and TLR4 stimulation. Our study, therefore, demonstrates that TBK1 is a target for dexamethasone, common to both TLR3 and TLR4 signaling.

IFNα and IFNω

No abstract is provided for this article.

2012 Editorial Board

No abstract is provided for this article.