Innate Immunity and Neurodegeneration Labzin, Larisa I; Heneka, Michael T; Latz, Eicke
Annual review of medicine,
01/2018, Volume:
69, Issue:
1
Journal Article
Peer reviewed
Open access
The innate immune system plays diverse roles in health and disease. It represents the first line of defense against infection and is involved in tissue repair, wound healing, and clearance of ...apoptotic cells and cellular debris. Excessive or nonresolving innate immune activation can lead to systemic or local inflammatory complications and cause or contribute to the development of inflammatory diseases. In the brain, microglia represent the key innate immune cells, which are involved in brain development, brain maturation, and homeostasis. Impaired microglial function, either through aberrant activation or decreased functionality, can occur during aging and during neurodegeneration, and the resulting inflammation is thought to contribute to neurodegenerative diseases. This review highlights recent advances in our understanding of the influence of innate immunity on neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease.
Programmed cell death is a critical host defence strategy during viral infection. Neighbouring cells deal with this death in distinct ways depending on how the infected cell dies. While apoptosis is ...considered immunologically silent, the lytic pathways of necroptosis and pyroptosis trigger inflammatory responses by releasing inflammatory host molecules. All these pathways have been implicated in influenza A virus infection. Here, we review how cells sense neighbouring infection and death and how sensing shapes ensuing inflammatory responses.
Methods for the targeted disruption of protein function have revolutionized science and greatly expedited the systematic characterization of genes. Two main approaches are currently used to disrupt ...protein function: DNA knockout and RNA interference, which act at the genome and mRNA level, respectively. A method that directly alters endogenous protein levels is currently not available. Here, we present Trim-Away, a technique to degrade endogenous proteins acutely in mammalian cells without prior modification of the genome or mRNA. Trim-Away harnesses the cellular protein degradation machinery to remove unmodified native proteins within minutes of application. This rapidity minimizes the risk that phenotypes are compensated and that secondary, non-specific defects accumulate over time. Because Trim-Away utilizes antibodies, it can be applied to a wide range of target proteins using off-the-shelf reagents. Trim-Away allows the study of protein function in diverse cell types, including non-dividing primary cells where genome- and RNA-targeting methods are limited.
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•Trim-Away is a widely applicable method to degrade endogenous proteins•Target proteins do not need to be modified before degradation•Proteins are degraded within minutes of application•Trim-Away allows efficient protein depletion in primary human cells
The cellular and molecular sources of elevated IL-1β and IL-6 in COVID-19 remain unclear. In this issue of Cell Host and Microbe, Barnett et al. determine how immune cells sense SARS-CoV-2 infection ...in neighboring epithelial cells to trigger inflammasome signaling and IL-1β release, which in turn promotes IL-6 release.
The cellular and molecular sources of elevated IL-1β and IL-6 in COVID-19 remain unclear. In this issue of Cell Host and Microbe, Barnett et al. determine how immune cells sense SARS-CoV-2 infection in neighboring epithelial cells to trigger inflammasome signaling and IL-1β release, which in turn promotes IL-6 release.
Interferons and the IL-1 family of cytokines have important roles in host defense against invading viruses and bacteria. Inflammasomes, multimeric cytosolic sensors of infection, are required for ...IL-1β and IL-18 processing and release. Interferons, IL-1β, and IL-18 are also implicated in autoimmune disease and chronic inflammation. Although independent but complementary pathways induce these cytokine subsets during infection, in some circumstances the cross-talk between these key inflammatory mediators is a particular requirement for effective host defense. In this review we will summarize recent discoveries concerning the potentiation of inflammasome responses by type I interferons, particularly in patients with gram-negative bacterial infections, and reflect on the molecular mechanisms of IFN-β's immunosuppressive effects through modulation of inflammasome and IL-1β signaling in patients with tuberculosis and multiple sclerosis.
Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease ...remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.
Acute inflammation is a critical host defense response during viral infection. When dysregulated, inflammation drives immunopathology and tissue damage. Excessive, damaging inflammation is a hallmark ...of both pandemic influenza A virus (IAV) infections and Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infections. Chronic, low-grade inflammation is also a feature of obesity. In recent years, obesity has been recognized as a growing pandemic with significant mortality and associated costs. Obesity is also an independent risk factor for increased disease severity and death during both IAV and SARS-CoV-2 infection. This review focuses on the effect of obesity on the inflammatory response in the context of viral respiratory infections and how this leads to increased viral pathology. Here, we will review the fundamentals of inflammation, how it is initiated in IAV and SARS-CoV-2 infection and its link to disease severity. We will examine how obesity drives chronic inflammation and trained immunity and how these impact the immune response to IAV and SARS-CoV-2. Finally, we review both medical and non-medical interventions for obesity, how they impact on the inflammatory response and how they could be used to prevent disease severity in obese patients. As projections of global obesity numbers show no sign of slowing down, future pandemic preparedness will require us to consider the metabolic health of the population. Furthermore, if weight-loss alone is insufficient to reduce the risk of increased respiratory virus-related mortality, closer attention must be paid to a patient’s history of health, and new therapeutic options identified.
Inflammasomes are potent innate immune signalling complexes that couple cytokine release with pro‐inflammatory cell death. However, pathogens have evolved strategies to evade this cell autonomous ...system. Here, we show how antibodies combine with innate sensors in primary human macrophages to detect viral infection and activate the inflammasome. Our data demonstrate that antibody opsonisation of virions can activate macrophages in multiple ways. In the first, antibody binding of adenovirus causes lysosomal damage, activating NLRP3 to drive inflammasome formation and IL‐1β release. Importantly, this mechanism enhances virion capture but not infection and is accompanied by cell death, denying the opportunity for viral replication. Unexpectedly, we also find that antibody‐coated viruses, which successfully escape into the cytosol, trigger a second system of inflammasome activation. These viruses are intercepted by the cytosolic antibody receptor TRIM21 and the DNA sensor cGAS. Together, these sensors stimulate both NLRP3 inflammasome formation and NFκB activation, driving dose‐dependent IL‐1β and TNF secretion, without inducing cell death. Our data highlight the importance of cooperativity between multiple sensing networks to expose viruses to the inflammasome pathway, which is particularly important for how our innate immune system responds to infection in the presence of pre‐existing immunity.
Synopsis
Antibodies enhance viral sensing by human macrophages and activate the inflammasome. Viruses routed to the lysosome induce cell death and IL‐1β release, while cytosolic viruses activate the Fc‐receptor TRIM21 and the cGAS/STING‐dependent NLRP3 inflammasome.
Antibodies potently activate the inflammasome in primary human macrophages during virus exposure.
Virus opsonization enhances virion uptake but not infection, resulting in lysosomal cell death and IL‐1β release.
Antibody‐bound viruses that infect the cytosol are detected by TRIM21, leading to capsid degradation and cGAS/STING – dependent NLRP3 inflammasome activation.
Viral infection promotes NLRP3 inflammasome activation via distinct pathways – one involving lysosomal damage‐mediated cell death, the other via cytosolic antibody receptor TRIM21 and innate immune sensor cGAS.
Cytokines and IFNs downstream of innate immune pathways are critical for mounting an appropriate immune response to microbial infection. However, the expression of these inflammatory mediators is ...tightly regulated, as uncontrolled production can result in tissue damage and lead to chronic inflammatory conditions and autoimmune diseases. Activating transcription factor 3 (ATF3) is an important transcriptional modulator that limits the inflammatory response by controlling the expression of a number of cytokines and chemokines. However, its role in modulating IFN responses remains poorly defined. In this study, we demonstrate that ATF3 expression in macrophages is necessary for governing basal IFN-β expression, as well as the magnitude of IFN-β cytokine production following activation of innate immune receptors. We found that ATF3 acted as a transcriptional repressor and regulated IFN-β via direct binding to a previously unidentified specific regulatory site distal to the Ifnb1 promoter. Additionally, we observed that ATF3 itself is a type I IFN-inducible gene, and that ATF3 further modulates the expression of a subset of inflammatory genes downstream of IFN signaling, suggesting it constitutes a key component of an IFN negative feedback loop. Consistent with this, macrophages deficient in Atf3 showed enhanced viral clearance in lymphocytic choriomeningitis virus and vesicular stomatitis virus infection models. Our study therefore demonstrates an important role for ATF3 in modulating IFN responses in macrophages by controlling basal and inducible levels of IFNβ, as well as the expression of genes downstream of IFN signaling.
Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn’s disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWASs) in UC implicate a FCGR2A ...variant that alters the binding affinity of the antibody receptor it encodes, FcγRIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in FcγRIIA affinity would affect inflammation in an IgA-dominated organ. We found a profound induction of anti-commensal IgG and a concomitant increase in activating FcγR signaling in the colonic mucosa of UC patients. Commensal-IgG immune complexes engaged gut-resident FcγR-expressing macrophages, inducing NLRP3- and reactive-oxygen-species-dependent production of interleukin-1β (IL-1β) and neutrophil-recruiting chemokines. These responses were modulated by the FCGR2A genotype. In vivo manipulation of macrophage FcγR signal strength in a mouse model of UC determined the magnitude of intestinal inflammation and IL-1β-dependent type 17 immunity. The identification of an important contribution of IgG-FcγR-dependent inflammation to UC has therapeutic implications.
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•Intestinal inflammation in UC is associated with increased anti-commensal IgG•Commensal-IgG cross-link FcγR on colonic MNPs, inducing IL-1β production•MNP FcγR A:I ratio determines magnitude of type 17 immunity and local inflammation•Identifies cellular mechanisms by which FcγRIIA H/R131 confers UC susceptibility
Castro-Dopico et al. find a profound induction of anti-commensal IgG in the colonic mucosa of UC patients and outline a pathway whereby FcγR receptor activation by IgG leads to IL-1β production, type 17 immunity, and the exacerbation of inflammation. Their findings reveal an important contribution of IgG-mediated inflammation in an IgA-dominated organ.
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