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Key Points NF-κB (nuclear factor-κB) activation is mediated by two main signalling pathways, the canonical and non-canonical pathways, which differ in both signalling mechanisms and biological functions. The canonical NF-κB pathway is stimulated by ligands of diverse immune receptors and involves the rapid and transient activation of IκB kinase (IKK), IKK-mediated IκBα phosphorylation, and subsequent IκBα degradation and nuclear translocation of canonical NF-κB members, including p50, RELA and c-REL. The non-canonical NF-κB pathway selectively responds to signals from a subset of tumour necrosis factor receptor (TNFR) superfamily members and involves slow and persistent activation of NF-κB-inducing kinase (NIK), NIK-mediated p100 phosphorylation, and subsequent p100 processing and nuclear translocation of non-canonical NF-κB members, including p52 and RELB. The non-canonical NF-κB pathway is tightly controlled by ubiquitin-dependent degradation of NIK mediated by an E3 ubiquitin ligase complex composed of cIAP family members, TNFR-associated factor 2 (TRAF2) and TRAF3; activation of non-canonical NF-κB involves signal-induced disruption of the cIAP E3 complex, typically via degradation of TRAF3, and accumulation of NIK. The non-canonical NF-κB pathway regulates important aspects of immune functions, including lymphoid organ development, the cross-priming function of dendritic cells, B cell survival and germinal centre reactions, generation and maintenance of effector and memory T cells, and antiviral innate immunity. The non-canonical NF-κB pathway is involved in various inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, kidney inflammation and injury, metabolic inflammation, and central nervous system inflammation. Defects in the non-canonical pathway of NF-κB activation are associated with severe immune deficiencies, and aberrant activation of this pathway can cause autoimmune and inflammatory diseases. Here, the author investigates the activation, signalling mechanisms and the biological function of the non-canonical NF-κB pathway. The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.

High circulating levels of lactate and high mobility group box-1 (HMGB1) are associated with the severity and mortality of sepsis. However, it is unclear whether lactate could promote HMGB1 release during sepsis. The present study demonstrated a novel role of lactate in HMGB1 lactylation and acetylation in macrophages during polymicrobial sepsis. We found that macrophages can uptake extracellular lactate via monocarboxylate transporters (MCTs) to promote HMGB1 lactylation via a p300/CBP-dependent mechanism. We also observed that lactate stimulates HMGB1 acetylation by Hippo/YAP-mediated suppression of deacetylase SIRT1 and β-arrestin2-mediated recruitment of acetylases p300/CBP to the nucleus via G protein-coupled receptor 81 (GPR81). The lactylated/acetylated HMGB1 is released from macrophages via exosome secretion which increases endothelium permeability. In vivo reduction of lactate production and/or inhibition of GPR81-mediated signaling decreases circulating exosomal HMGB1 levels and improves survival outcome in polymicrobial sepsis. Our results provide the basis for targeting lactate/lactate-associated signaling to combat sepsis.

Key Points Immunometabolism describes the changes that occur in intracellular metabolic pathways in immune cells during activation. Six major pathways have been studied in immune cells in detail: glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism. Glycolysis and fatty acid synthesis are key features of lipopolysaccharide (LPS)-activated macrophages; by contrast, interleukin-4 (IL-4)-activated macrophages mainly use oxidative phosphorylation and fatty acid oxidation to generate energy. Effector T cells are highly glycolytic whereas memory T cells have an oxidative metabolism. Metabolites, such as succinate and citrate, and enzymes, such as pyruvate kinase isoenzyme M2 (PKM2), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and enolase, have roles outside of metabolism that promote specific events during immune cell activation. Small molecules can target metabolic pathways and alter the phenotype of immune cells, raising the possibility of therapeutic intervention Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.

Diseases associated with chronic inflammation constitute a major health burden across the world. As central instigators of the inflammatory response to infection and tissue damage, inflammasomes — and the NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome in particular — have emerged as key regulators in diverse rheumatic, metabolic and neurodegenerative diseases. Similarly to other inflammasome sensors, NLRP3 assembles a cytosolic innate immune complex that activates the cysteine protease caspase-1, which in turn cleaves gasdermin D (GSDMD) to induce pyroptosis, a regulated mode of lytic cell death. Pyroptosis is highly inflammatory, partly because of the concomitant extracellular release of the inflammasome-dependent cytokines IL-1β and IL-18 along with a myriad of additional danger signals and intracellular antigens. Here, we discuss how NLRP3 and downstream inflammasome effectors such as GSDMD, apoptosis-associated speck-like protein containing a CARD (ASC) and nerve injury-induced protein 1 (NINJ1) have gained significant traction as therapeutic targets. We highlight the recent progress in developing small-molecule and biologic inhibitors that are advancing into the clinic and serving to harness the broad therapeutic potential of modulating the NLRP3 inflammasome.Inflammasomes are central instigators of the inflammatory response to infection and tissue damage and key regulators in diverse diseases. Here, the authors describe signalling mechanisms that regulate the NLRP3 inflammasome pathways and recent progress in the development of inhibitors and agonists that are advancing into the clinic.

Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis. DFNA5 is related to the caspase-dependent pyroptosis inducer gasdermin D. Here the authors find that DFNA5 is cleaved by caspase 3 and show this cleavage skews cells away from apoptosis into secondary necrosis, a form of cell death characterized by membrane ballooning similar to pyroptosis.

Beyaert, Karin and colleagues discuss the key molecular mechanisms that contribute to the self-limiting nature of inflammatory signaling, with emphasis on the negative regulation of the NF-κB pathway and the NLRP3 inflammasome. A properly mounted immune response is indispensable for recognizing and eliminating danger arising from foreign invaders and tissue trauma. However, the 'inflammatory fire' kindled by the host response must be tightly controlled to prevent it from spreading and causing irreparable damage. Accordingly, acute inflammation is self-limiting and is normally attenuated after elimination of noxious stimuli, restoration of homeostasis and initiation of tissue repair. However, unresolved inflammation may lead to the development of chronic autoimmune and degenerative diseases and cancer. Here, we discuss the key molecular mechanisms that contribute to the self-limiting nature of inflammatory signaling, with emphasis on the negative regulation of the NF-κB pathway and the NLRP3 inflammasome. Understanding these negative regulatory mechanisms should facilitate the development of much-needed therapeutic strategies for treatment of inflammatory and autoimmune pathologies.

Immune signalling pathways convert pathogenic stimuli into cytosolic events that lead to the resolution of infection. Upon ligand engagement, immune receptors together with their downstream adaptors and effectors undergo substantial conformational changes and spatial reorganization. During this process, nanometre-to-micrometre-sized signalling clusters have been commonly observed that are believed to be hotspots for signal transduction. Because of their large size and heterogeneous composition, it remains a challenge to fully understand the mechanisms by which these signalling clusters form and their functional consequences. Recently, phase separation has emerged as a new biophysical principle for organizing biomolecules into large clusters with fluidic properties. Although the field is still in its infancy, studies of phase separation in immunology are expected to provide new perspectives for understanding immune responses. Here, we present an up-to-date view of how liquid–liquid phase separation drives the formation of signalling condensates and regulates immune signalling pathways, including those downstream of T cell receptor, B cell receptor and the innate immune receptors cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and retinoic acid-inducible gene I protein (RIG-I). We conclude with a summary of the current challenges the field is facing and outstanding questions for future studies.Phase separation has emerged as a new biophysical principle for organizing biomolecules into large clusters with fluidic properties. Here, Su and colleagues summarize what we currently know about phase separation in immune cells and look to the future of this field in understanding the regulation of immune signalling.

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca 2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway. STIM1 is a calcium sensor that is essential for functional lymphocyte responses. Gwack and colleagues demonstrate a calcium-independent role for STIM1 in macrophages that regulates their production of type I interferons.

Key Points ATP, ADP and other nucleotides can be released by stressed or apoptotic cells into the extracellular environment. They function as autocrine and paracrine signalling molecules by activating cell-surface purinergic receptors. Activation of purinergic signalling pathways can have both pro- and anti-inflammatory effects. During the acute stages of tissue injury, purinergic signalling can promote the recruitment and activation of leukocytes to the damaged site. At later times, purinergic signalling dampens inflammation and promotes wound healing. Drugs that target purinergic receptors are being developed as potential therapeutics to treat patients with inflammatory disorders, autoimmune diseases or cancer. This Review focuses on how purinergic signalling pathways regulate both innate and adaptive immune responses. The authors discuss the potential of targeting purinergic signalling pathways for the treatment of ischaemia, organ transplantation, autoimmunity and cancer. Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.

The cytokine IL-7 and its receptor, IL-7R, are critical for T cell and, in the mouse, B cell development, as well as differentiation and survival of naive T cells, and generation and maintenance of memory T cells. They are also required for innate lymphoid cell (ILC) development and maintenance, and consequently for generation of lymphoid structures and barrier defense. Here we discuss the central role of IL-7 and IL-7R in the lymphoid system and highlight the impact of their deregulation, placing a particular emphasis on their ‘dark side’ as promoters of cancer development. We also explore therapeutic implications and opportunities associated with either positive or negative modulation of the IL-7–IL-7R signaling axis. The cytokine IL-7 plays essential roles in lymphocyte development. In their Review, Barata, Durum and Seddon describe IL-7’s key homeostatic functions and how its dysregulation can lead to autoinflammatory disease and cancer.