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Circadian rhythms are a ubiquitous feature of virtually all living organisms, regulating a wide diversity of physiological systems. It has long been established that the circadian clockwork plays a key role in innate immune responses, and recent studies reveal that several aspects of adaptive immunity are also under circadian control. We discuss the latest insights into the genetic and biochemical mechanisms linking immunity to the core circadian clock of the cell and hypothesize as to why the immune system is so tightly controlled by circadian oscillations. Finally, we consider implications for human health, including vaccination strategies and the emerging field of chrono-immunotherapy.

Inflammasomes are important sentinels of innate immune defence, sensing pathogens and inducing cell death in infected cells 1 . There are several inflammasome sensors that each detect and respond to a specific pathogen- or damage-associated molecular pattern (PAMP or DAMP, respectively) 1 . During infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which can simultaneously engage multiple inflammasome sensors 2 – 5 . Here we found that AIM2 regulates the innate immune sensors pyrin and ZBP1 to drive inflammatory signalling and a form of inflammatory cell death known as PANoptosis, and provide host protection during infections with herpes simplex virus 1 and Francisella novicida . We also observed that AIM2, pyrin and ZBP1 were members of a large multi-protein complex along with ASC, caspase-1, caspase-8, RIPK3, RIPK1 and FADD, that drove inflammatory cell death (PANoptosis). Collectively, our findings define a previously unknown regulatory and molecular interaction between AIM2, pyrin and ZBP1 that drives assembly of an AIM2-mediated multi-protein complex that we term the AIM2 PANoptosome and comprising multiple inflammasome sensors and cell death regulators. These results advance the understanding of the functions of these molecules in innate immunity and inflammatory cell death, suggesting new therapeutic targets for AIM2-, ZBP1- and pyrin-mediated diseases. AIM2 responds to infection with herpes simplex virus 1 or Francisella novicida by driving assembly of a large multi-protein complex containing multiple inflammasome sensors and cell death regulators.

Innate lymphoid cells (ILCs) have key roles in immune responses, lymphoid tissue development and tissue regeneration. Recently, several new ILC subsets were identified. Here, the authors propose the use of a uniform nomenclature to describe all ILC subsets to avoid confusion and further promote the development of this field. Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.

Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides that are released during bacterial infection and in endogenous cyclic GMP–AMP signalling during viral infection and anti-tumour immunity 1 – 5 . STING shares no structural homology with other known signalling proteins 6 – 9 , which has limited attempts at functional analysis and prevented explanation of the origin of cyclic dinucleotide signalling in mammalian innate immunity. Here we reveal functional STING homologues encoded within prokaryotic defence islands, as well as a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to cyclic di-GMP synthesized by a neighbouring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple the recognition of cyclic dinucleotides with the formation of protein filaments to drive oligomerization of TIR effector domains and rapid NAD + cleavage. We reconstruct the evolutionary events that followed the acquisition of STING into metazoan innate immunity, and determine the structure of a full-length TIR–STING fusion from the Pacific oyster Crassostrea gigas . Comparative structural analysis demonstrates how metazoan-specific additions to the core STING scaffold enabled a switch from direct effector function to regulation of antiviral transcription. Together, our results explain the mechanism of STING-dependent signalling and reveal the conservation of a functional cGAS–STING pathway in prokaryotic defence against bacteriophages. Structures of prokaryotic homologues of STING permit the reconstruction of the evolutionary trajectory of its incorporation into metazoan innate immunity, and reveal a role for the conserved cGAS–STING pathway in prokaryotic defence against bacteriophages.

Key Points Reverse cholesterol transport is a process by which cholesterol is transferred from peripheral cells, including macrophages, to the liver for excretion. The acute phase response results in suppression of reverse cholesterol transport at multiple steps, which may in turn promote cholesterol accumulation in macrophages and other immune cells. This can lead to a beneficial enhancement of inflammatory responses in the setting of infection, but when inflammation becomes prolonged these changes may worsen conditions such as atherosclerosis and obesity. During the acute phase response, high-density lipoprotein (HDL) levels are decreased and compositional changes in HDL, including myeloperoxidase-mediated modifications of apolipoprotein A1 (APOA1), may convert HDL into a dysfunctional form that cannot efficiently mediate cholesterol efflux and that becomes pro-inflammatory. Although these changes in HDL and APOA1 are probably pro-atherogenic, they may also have a physiological function in the setting of infection by enhancing the inflammatory response. Liver X receptor (LXR) transcription factors promote reverse cholesterol transport by inducing the expression of genes involved in cellular cholesterol efflux, transport in the bloodstream and excretion in the liver. The mechanisms connecting inflammation with decreases in reverse cholesterol transport include the ability of endotoxins to suppress the expression of LXR and its partner retinoid X recceptor (RXR), as well as the suppression of cellular LXR responses via a trans -repression mechanism. The mechanisms of pro-inflammatory effects of cellular cholesterol accumulation include enhanced Toll-like receptor (TLR) signalling and inflammasome activation. Inflammasome activation may be stimulated by cholesterol crystal uptake or formation in macrophages. Conversely, the induction of cholesterol 25-hydroxylase by lipopolysaccharide and type I interferons opposes inflammasome activation, probably because 25-hydroxycholesterol suppresses cellular sterol synthesis. Defective cholesterol efflux promotes monocyte and neutrophil production in the bone marrow and the spleen, involving the proliferation of haematopoietic stem cells (HSCs) and myeloid progenitor cells, mobilization of HSCs and extramedullary haematopoiesis. Although these pathways probably enhance the response to infections, genetic suppression and dietary challenge lead to aberrant responses that promote atherogenesis. Therapeutic interventions such as increased production or infusion of HDL may sever the links between cholesterol accumulation and inflammation with benefits for metabolic diseases. This may involve infusions of cholesterol-poor reconstituted HDL or targeting the APOA1 gene locus to increase endogenous APOA1 production. The accumulation of cholesterol in macrophages and other immune cells promotes inflammatory responses. Inflammation, in turn, reduces the normal physiological excretion of cholesterol, which amplifies the inflammatory response and promotes myelopoiesis. Here, the authors detail the mechanisms by which cholesterol accumulation affects immune signalling pathways and highlight potential therapeutic interventions that may have benefits for metabolic diseases. Hypercholesterolaemia leads to cholesterol accumulation in macrophages and other immune cells, which promotes inflammatory responses, including augmentation of Toll-like receptor (TLR) signalling, inflammasome activation, and the production of monocytes and neutrophils in the bone marrow and spleen. On a cellular level, activation of TLR signalling leads to decreased cholesterol efflux, which results in further cholesterol accumulation and the amplification of inflammatory responses. Although cholesterol accumulation through the promotion of inflammatory responses probably has beneficial effects in the response to infections, it worsens diseases that are associated with chronic metabolic inflammation, including atherosclerosis and obesity. Therapeutic interventions such as increased production or infusion of high-density lipoproteins may sever the links between cholesterol accumulation and inflammation, and have beneficial effects in patients with metabolic diseases.

Osteoarthritis (OA) is a chronic progressive disease of the joint. Although representing the most frequent cause of disability in the elderly, OA remains partly obscure in its pathogenic mechanisms and is still the orphan of resolutive therapies. The concept of what was once considered a “wear and tear” of articular cartilage is now that of an inflammation-related disease that affects over time the whole joint. The attention is increasingly focused on the synovium. Even from the earliest clinical stages, synovial inflammation (or synovitis) is a crucial factor involved in OA progression and a major player in pain onset. The release of inflammatory molecules in the synovium mediates disease progression and worsening of clinical features. The activation of synovial tissue-resident cells recalls innate immunity cells from the bloodstream, creating a proinflammatory milieu that fuels and maintains a damaging condition of low-grade inflammation in the joint. In such a context, cellular and molecular inflammatory behaviors in the synovium could be the primum movens of the structural and functional alterations of the whole joint. This paper focuses on and discusses the involvement of innate immunity cells in synovitis and their role in the progression of OA.

The etiopathogenesis of systemic lupus erythematosus (SLE), a clinically heterogeneous multisystemic syndrome that derives its name from the initial characterization of facial lesions that resemble the bite of a wolf, is considered a complex, multifactorial interplay between underlying genetic susceptibility factors and the environment. Prominent pathogenic factors include the induction of aberrant cell death pathways coupled with defective cell death clearance mechanisms that promote excessive externalization of modified cellular and nuclear debris with subsequent loss of tolerance to a wide variety of autoantigens and innate and adaptive immune dysregulation. While abnormalities in adaptive immunity are well recognized and are key to the pathogenesis of SLE, recent findings have emphasized fundamental roles of the innate immune system in the initiation and propagation of autoimmunity and the development of organ damage in this disease. This Review focuses on recent discoveries regarding the role of components of the innate immune system, specifically neutrophils and interferons, in promoting various aspects of lupus pathogenesis, with potential implications for novel therapeutic strategies.

Background Rubella primary infection during early stages of pregnancy is associated with high risk of congenital Rubella syndrome (CRS). Prevention of CRS in the resource-limited countries requires multiple strategies. Here, we document the data on the magnitude of Rubella natural immunity among adolescent girls which is a crucial group in devising effective control strategies to prevent CRS. Methods A cross sectional study involving 397 adolescent girls was conducted in the city of Mwanza involving five secondary schools. Socio-demographic and other relevant information were collected using pre-tested data collection tool. Rubella IgG antibodies were determined using enzyme immunoassay. The presence of Rubella IgG titers of >10 IU/ml indicated natural immunity. Results The mean age of the study participants was 15.18 ± 1.48 years. Of 397 girls, 340 (85.6%) and 57 (14.4%) were from secondary schools representing peri-urban and rural areas, respectively. Out of 397 girls, 90.4% (95% CI: 87-93) were found to be naturally immune with median Rubella IgG antibodies titers of 56.7 IU/ml interquartile range (IQR): 40.8-137. The median Rubella IgG antibodies titers were significantly high in adolescent girls from families with high socio-economic status (63.96 vs. 47.13 IU/ml, P  < 0.001) and in adolescent girls from peri-urban areas of the city (63.33 vs. 39.9 IU/ml, P < 0.001). Conclusion The majority of adolescent girls in the city of Mwanza are naturally immune to Rubella virus. There is a need to compare the effectiveness of screening and vaccinating susceptible adolescent girls with the effectiveness of vaccinating all women of childbearing in controlling CRS in low-income countries.

Key Points Invariant natural killer T (iNKT) cells are a specialized T cell population that recognizes lipid antigens that are presented by a cell-surface molecule known as CD1d. They have been shown to have important roles in many diverse immune responses. iNKT cells recognize both foreign lipid antigens and self lipid antigens. The T cell receptor (TCR)–lipid–CD1d interaction is similar for both self and foreign lipid antigens, despite the differences that exist in these lipid structures. Strong lipid antigens have a 'lock and key' type of binding, whereas weaker antigens require an 'induced fit' mechanism. The production of lipid self antigens for iNKT cells can be upregulated by antigen-presenting cells (APCs) in response to danger signals, such as Toll-like receptor (TLR) agonists. This provides a mechanism for iNKT cell activation in the absence of foreign lipid antigens. In addition to being activated through their TCRs in response to CD1d-presented lipids, iNKT cells can be activated by indirect stimuli, such as pro-inflammatory cytokines. During many infections, interleukin-12 (IL-12) may have an equally important role to lipid antigens in activating iNKT cells. iNKT cells couple the rapid activation kinetics of innate immune cells with the diverse effector functions of adaptive T cells. Early activation during infection leads to rapid cytokine production in target tissues by polarized iNKT cell subsets. Interactions between iNKT cells and CD1d-expressing APCs lead to bidirectional activation. Cytokines produced by iNKT cells activate and recruit other cell types early during immune responses, while activated APCs direct the ensuing adaptive immune responses. Thus, iNKT cells and their lipid antigens help to orchestrate innate and adaptive immune responses. Invariant natural killer T (iNKT) cells are innate-like lymphocytes that express T cell receptors that can be activated by lipid antigens presented on CD1d molecules. Here, the authors describe different models of iNKT cell activation and discuss how activated iNKT cells can contribute to both protective and pathological immune responses. Invariant natural killer T (iNKT) cells exist in a 'poised effector' state, which enables them to rapidly produce cytokines following activation. Using a nearly monospecific T cell receptor, they recognize self and foreign lipid antigens presented by CD1d in a conserved manner, but their activation can catalyse a spectrum of polarized immune responses. In this Review, we discuss recent advances in our understanding of the innate-like mechanisms underlying iNKT cell activation and describe how lipid antigens, the inflammatory milieu and interactions with other immune cell subsets regulate the functions of iNKT cells in health and disease.

Key Points Mitogen-activated protein kinases (MAPKs) in innate immune cells are activated by a range of pattern recognition receptors, of which the best studied are Toll-like receptors (TLRs). TLR ligation induces the formation of a signalling complex that includes IL-1R-associated kinases (IRAKs) and TNFR-associated factor 6 (TRAF6), which is mediated by K63-linked polyubiquitylation. This complex interacts with and activates TGFβ-activated kinase 1 (TAK1), a MAPK kinase kinase (MAP3K) upstream of p38α and Jun N-terminal kinases (JNKs). TAK1 can also activate the IκB kinase (IKK) complex, leading to the activation of the transcription factor nuclear factor-κB and the MAP3K tumour progression locus 2 (TPL2), which is upstream of extracellular signal-regulated kinase 1 (ERK1) and ERK2. Recent genetic evidence, however, has shown that TAK1 is not required for TLR activation of MAPKs in primary macrophages, and the MAP3K involved remains to be identified. MAPK signalling has several of roles in innate immune responses, ranging from the induction of pro-inflammatory mediators, such as cytokines and chemokines, to the activation of anti-inflammatory feedback pathways. MAPKs can activate downstream kinases that have crucial roles in immunity; for example, p38α activates MAPK-activated protein kinase 2 (MK2), which promotes tumour necrosis factor (TNF) production. By contrast, the activation of mitogen- and stress-activated kinases (MSKs) by p38α or by ERK1 and ERK2 results in the increased transcription of the anti-inflammatory cytokines interleukin-10 (IL-10) and IL-1 receptor antagonist (IL-1RA). MAPK signalling induces the expression of dual specificity phosphatases (DUSPs). This establishes a negative feedback loop, in which the DUSPs dephosphorylate and inactivate MAPKs. Genetic studies have shown the crucial role of DUSPs in controlling innate immune responses. Bacterial pathogens have evolved ways to directly target MAPKs to downregulate the host immune response; for example, distinct bacterial proteins have been shown to inhibit MAPK signalling by inactivating MAPK kinase (MKK) enzymes and by activating DUSPs. Small-molecule inhibitors which target MAPK signalling have the potential to function as anti-inflammatory drugs. p38 inhibitors were the first MAPK inhibitors to be developed, but clinical results from using these compounds have been disappointing. As a result, focus in the pharmaceutical industry has shifted to targeting upstream MAP3Ks or downstream kinases, such as MK2. This Review summarizes our current understanding of the regulation and function of mitogen-activated protein kinases (MAPKs) in innate immunity, as well as the mechanisms by which pathogens manipulate MAPK activation and the potential of targeting MAPK pathways for the treatment of inflammatory diseases. Following pathogen infection or tissue damage, the stimulation of pattern recognition receptors on the cell surface and in the cytoplasm of innate immune cells activates members of each of the major mitogen-activated protein kinase (MAPK) subfamilies — the extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK) subfamilies. In conjunction with the activation of nuclear factor-κB and interferon-regulatory factor transcription factors, MAPK activation induces the expression of multiple genes that together regulate the inflammatory response. In this Review, we discuss our current knowledge about the regulation and the function of MAPKs in innate immunity, as well as the importance of negative feedback loops in limiting MAPK activity to prevent host tissue damage. We also examine how pathogens have evolved complex mechanisms to manipulate MAPK activation to increase their virulence. Finally, we consider the potential of the pharmacological targeting of MAPK pathways to treat autoimmune and inflammatory diseases.