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Gain-of-function variants in the gene encoding NLRP3 lead to constitutive inflammasome activation and excessive IL-1β production. In this resource, authors perform functional screening of clinically relevant NLRP3 variants. Structural analysis suggested multiple mechanisms by which variants activate NLRP3 and the identification of pathogenic variants that can sensitize the activation of NLRP3 in response to nigericin and cold temperature exposure.

The RNA exonuclease REXO2 plays an important role in the degradation of mitochondrial RNA. Authors here describe a dominant negative REXO2 mutation that causes autoinflammatory disease via Type I IFN activation.

Rare genetic variants in UNC93B1 predispose to childhood-onset lupus via TLR7/-8–IRAK1/-4, validated with a corresponding mouse model.

Mutations in the coatomer complex I can result in endoplasmic reticulum stress and inflammatory consequences. Here authors define aberrant activation of the STING immunosensing pathway in a disturbed coatmer complex context and the therapeutic modulation of this axis to counter the associated immunopathology.

Monogenic disorders involving key elements of the TNF pathway now encompass a diverse and expanding group of conditions, spanning autoinflammatory, autoimmune, immunodeficiency and neurodegenerative diseases. This Review discusses the genetic causes, clinical features and current therapeutic strategies for these disorders, emphasizing the value of accurate molecular diagnosis and targeted interventions.

Heterozygous mutateons in the caspase-8 cleavage site of RIPK1 cause a range of autoinflammatory symptoms in humans, and caspase-8 cleavage of RIPK1 in a mouse model limits TNF-induced cell death and inflammation.

APLAID is a rare autoinflammatory disorder driven by mutations in PLCG2. Here the authors provide a new mouse model using the human APLAID p.Ser707Tyr mutation. The mouse recapitulates clinical features of APLAID that can be prevented by anti-G-CSF. Individuals with APLAID were also shown to have high circulating levels of G-CSF suggesting this might be a suitable target for the clinic.

Innate immune responses are triggered in response to the sensing of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs). An emerging idea is that inflammasome activation may also occur independently of PRR activation following a disturbance in cellular homeostasis. The authors explore this concept and the implications for chronic inflammatory disease in this Opinion article.

Eitan et al. discovered genetic variants in the 3′UTR for the gene encoding IL-18 receptor that protect against ALS. The variant 3′UTR destabilizes the mRNA and dampens microglia NF-κB signaling and neurotoxicity, thus emphasizing the value of noncoding genetic association studies.

The inflammasome is normally activated by pathogens to induce tissue inflammation. Here the authors show that, in mouse experimental colitis models, Nlrp1 inflammasome sensor activates IL-18 to reduce beneficial colonic Clostridiales species, thereby decreasing microbial butyrate and its protective effects on colitis.

Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.

RIPK3 can cause necroptotic cell death via MLKL phosphorylation, and activate NLRP3 inflammasome. Here the authors show that MLKL is dispensable for NLRP3 activation by RIPK3, and highlight how different IAP proteins limit RIPK3 induced apoptosis, necroptosis and IL-1 secretion.

Pancreatic islets in type 2 diabetes show characteristic deposition of the amyloid polypeptide IAPP. O'Neill and colleagues show that IAPP induces IL-1β production via the NLRP3 inflammasome, which leads to beta-cell destruction.

Obesity-associated inflammation is restrained by regulatory T cells present in visceral fat. Kallies and colleagues show interleukin 33 and the transcription factors BATF and IRF4 are necessary to maintain visceral adipose tissue T_reg cells.

The NLRP10 protein is found to form an inflammasome complex in response to mitochondrial damage. Loss of NLRP10 from colonic epithelia promotes inflammatory bowel disease in a mouse model, while a variant predisposing to atopic dermatitis also shows loss of function.

A selective, small-molecule inhibitor of NLRP3 suppresses activation of the inflammasome in vitro and in vivo and attenuates inflammatory disease.

This Review from Masters and colleagues highlights how damage to intracellular organelles is linked to activation of the innate immune system. The authors propose that a better appreciation of such organellar homeostasis could lead to the identification of novel innate immune pathways and have therapeutic implications.

Enteropathogenic Escherichia coli EspL is a cysteine protease that cleaves RHIM-containing proteins and blocks inflammasome signalling during infection.

Constitutive innate immune mechanisms, such as restriction factors, RNA interference, antimicrobial peptides, basal autophagy and proteasomal degradation, exert early host defence activities that also aim to minimize tissue damage and homeostatic disruption by limiting the activation of inducible innate immunity.

Non-invasive liquid biopsies such as plasma circulating tumour DNA (ctDNA) and urinary tumour DNA (utDNA) are promising tools for urothelial carcinoma diagnosis and management. In this Review, the authors provide an overview of the different liquid biopsy technologies available, and discuss the current state as well as future perspectives of ctDNA and utDNA application in urothelial carcinoma clinical care.

Immunotherapy is associated with durable clinical benefit in patients with melanoma, and this consensus statement outlines recommendations for its use. The panel has based their guidance on the available evidence and outlines a treatment paradigm using drugs that are FDA approved.