Microglia-Derived Interleukin 23: A Crucial Cytokine in Alzheimer's Disease?
Ontology highlight
ABSTRACT:
SUBMITTER: Nitsch L
PROVIDER: S-EPMC8058463 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Interleukin (IL)-37, a new IL-1 family member, has received increasing attention in recent years. In the past decade, it has been determined that IL-37 is expressed in various normal cells and tissues and is regulated by inflammatory stimuli and pro-cytokines via different signal transduction pathways. Recently, it has been found that IL-37 is expressed in a variety of cancers, chronic inflammatory and autoimmune disorders, and exerts anti-inflammatory effects. Moreover, a growing body of literature demonstrates that IL-37 plays a vital role in inhibiting both innate and adaptive immune responses as well as inflammatory reactions. In addition, IL-37 may prove to be a new and potentially useful target for effective cytokine therapy. Further evidence is needed to clarify in more detail the effects of IL-37 in experimental and clinical studies. Based on an extensive summary of published data, the aim of this review is to outline the current knowledge of IL-37, including the location, structure, expression, regulation and function, as well as the potential clinical applications of this cytokine.
| S-EPMC5840652 | biostudies-literature
Project description:: Crohn's disease (CD) is a lifelong inflammatory condition with underlying environmental and genetic components. CD affects multiple parts of the gastrointestinal tract, and it has a growing incidence in Western societies. IL-23 receptor variants have been identified as susceptibility or resistance factors for CD in genome-wide association studies. Accordingly, IL-23 is required for the development of experimental inflammatory bowel disease in many murine models. IL-23 receptor is expressed by both innate and adaptive immune cells, which include Th17, natural killer T, ?? T cells, and ROR?t innate lymphoid cells all of which are capable of secreting IL-17A, IL-17F, IL-22, and interferon-? upon IL-23 stimulation. During the past decade, pathogenic and protective roles have been described for these cytokines in the inflammatory bowel disease pathogenesis. More recently, innate lymphoid cells have been implicated in disease development. In this review, we have summarized and discussed these findings with an emphasis not only on the contribution of Th17 but also on innate lymphoid cells to disease etiology.
| S-EPMC3966024 | biostudies-literature
Project description:BackgroundAutophagy is a major pathway of protein and organelle degradation in the lysosome. Autophagy exists at basal constitutive level and can be induced as a defense mechanism under stress conditions. Molecular relationships between autophagy and inflammation at the periphery were recently evidenced, highlighting a role of autophagy in the regulation of inflammation. Impairment of autophagy (with accumulation of autophagic vacuoles) and substantial inflammation are found in neurodegenerative diseases such as Alzheimer's Disease (AD). However, the links between autophagy and inflammation in AD remain to be determined.MethodsHere, we examined the inflammatory reaction and autophagy in murine tri-cultures of neurons, astrocytes, and microglia. Tri-cultures were exposed to various inflammatory stresses (lipopolysaccharide (LPS), amyloid peptide (A?42) with or without cytokines) for 48 hours. Furthermore, the relationships between inflammation and autophagy were also analyzed in astrocyte- and microglia-enriched cultures. Data for multiple variable comparisons were analyzed by a one-way ANOVA followed by a Newman-keuls' test.ResultsA?42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1?, TNF-?, and IL-6) or IL-1? alone which led to co-localization of p62 and LC3, two markers of autophagy, with acidic vesicles stained with Lyso-ID Red dye. Moreover, the study reveals a major role of IL-1? in the induction of autophagy in tri-cultures in the presence or absence of A?42. However, the vulnerability of the autophagic process in purified microglia to IL-1? was prevented by A?42.ConclusionThese findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1? in the induction of the microglial autophagy which could be the case in AD. New therapeutic strategies could target inflammasome and autophagy in microglia to maintain its role in the amyloid immunosurveillance.
| S-EPMC3878742 | biostudies-literature
Project description:Pathological aggregation of amyloid-β (Aβ) is a main hallmark of Alzheimer's disease (AD). Recent genetic association studies have linked innate immune system actions to AD development, and current evidence suggests profound gender differences in AD pathogenesis. Here, we characterise gender-specific pathologies in the APP23 AD-like mouse model and find that female mice show stronger amyloidosis and astrogliosis compared with male mice. We tested the gender-specific effect of lack of IL12p40, the shared subunit of interleukin (IL)-12 and IL-23, that we previously reported to ameliorate pathology in APPPS1 mice. IL12p40 deficiency gender specifically reduces Aβ plaque burden in male APP23 mice, while in female mice, a significant reduction in soluble Aβ1-40 without changes in Aβ plaque burden is seen. Similarly, plasma and brain cytokine levels are altered differently in female versus male APP23 mice lacking IL12p40, while glial properties are unchanged. These data corroborate the therapeutic potential of targeting IL-12/IL-23 signalling in AD, but also highlight the importance of gender considerations when studying the role of the immune system and AD.
| S-EPMC7054677 | biostudies-literature
Project description:Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer's disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.
| S-EPMC5800817 | biostudies-literature
Project description:Pathological aggregation of amyloid-? (A?) is a main hallmark of Alzheimer's disease (AD). Recent genetic association studies have linked innate immune system actions to AD development and current evidence suggests profound gender differences in AD pathogenesis. Here, we characterise gender-specific pathologies in the APP23 AD-like mouse model and find that female mice show stronger amyloidosis and astrogliosis compared with male mice. We tested the gender-specific effect of lack of IL12p40, the shared subunit of interleukin (IL)-12 and IL-23, that we previously reported to ameliorate pathology in APPPS1 mice. IL12p40 deficiency gender-specifically reduces A? plaque burden in male APP23 mice, while in female mice a significant reduction of soluble A?1-40 without changes in A? plaque burden is seen. Similarly, plasma and brain cytokine levels are altered differently in female versus male APP23 mice lacking IL12p40, while glial properties are unchanged. These data corroborate the therapeutic potential of targeting IL-12/IL-23 signalling in AD, but also highlight the importance of gender considerations when studying the role of the immune system and AD.-
| S-SCDT-EMBOR-2019-48530V1 | biostudies-other
Project description:Microglia, the immune cell of the brain, are implicated in cascades leading to neuronal loss and cognitive decline in Alzheimer's disease (AD). Recent genome-wide association studies have indicated a number of risk factors for the development of late-onset AD. Two of these risk factors are an altered immune response and polymorphisms in complement receptor 1. In view of these findings, we discuss how complement signalling in the AD brain and microglial responses in AD intersect. Dysregulation of the complement cascade, either by changes in receptor expression, enhanced activation of different complement pathways or imbalances between complement factor production and complement cascade inhibitors may all contribute to the involvement of complement in AD. Altered complement signalling may reduce the ability of microglia to phagocytose apoptotic cells and clear amyloid beta peptides, modulate the expression by microglia of complement components and receptors, promote complement factor production by plaque-associated cytokines derived from activated microglia and astrocytes, and disrupt complement inhibitor production. The evidence presented here indicates that microglia in AD are influenced by complement factors to adopt protective or harmful phenotypes and the challenge ahead lies in understanding how this can be manipulated to therapeutic advantage to treat late onset AD.
| S-EPMC3432348 | biostudies-literature
Project description:Multiple cellular systems exist to prevent uncontrolled inflammation in brain tissues; the suppressor of cytokine signaling (SOCS) proteins have key roles in these processes. SOCS proteins are involved in restricting cellular signaling pathways by enhancing the degradation of activated receptors and removing the stimuli for continued activation. There are eight separate SOCS genes that code for proteins with similar structures and properties. All SOCS proteins can reduce signaling of activated transcription factors Janus kinase (JAK) and signal transducer and activator of transcription (STAT), but they also regulate many other signaling pathways. SOCS-1 and SOCS-3 have particular roles in regulating inflammatory processes. Chronic inflammation is a key feature of the pathology present in Alzheimer's disease (AD)-affected brains resulting from responses to amyloid plaques or neurofibrillary tangles, the pathological hallmarks of AD. The goal of this study was to examine SOCS gene expression in human non-demented (ND) and AD brains and in human brain-derived microglia to determine if AD-related pathology resulted in a deficit of these critical molecules. We demonstrated that SOCS-1, SOCS-2, SOCS-3 and cytokine-inducible SH2 containing protein (CIS) mRNA expression was increased in amyloid beta peptide (Aβ)- and inflammatory-stimulated microglia, while SOCS-6 mRNA expression was decreased by both types of treatments. Using human brain samples from the temporal cortex from ND and AD cases, SOCS-1 through SOCS-7 and CIS mRNA and SOCS-1 through SOCS-7 protein could be detected constitutively in ND and AD human brain samples. Although, the expression of key SOCS genes did not change to a large extent as a result of AD pathology, there were significantly increased levels of SOCS-2, SOCS-3 and CIS mRNA and increased protein levels of SOCS-4 and SOCS-7 in AD brains. In summary, there was no evidence of a deficit of these key inflammatory regulating proteins in aged or AD brains.
| S-EPMC4385752 | biostudies-literature
Project description:Genetic and genome-wide association studies suggest a central role for microglia in Alzheimer's disease (AD). However, single-cell RNA sequencing (scRNA-seq) of microglia in mice, a key preclinical model, has shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains (WSB/EiJ, CAST/EiJ, and PWK/PhJ) with and without APP/PS1 demonstrates that genetic diversity significantly alters features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. Results show significant variation in the abundance of microglial subtypes or states, including numbers of previously identified disease-associated and interferon-responding microglia, across the strains. For each subtype, significant differences in the expression of many genes are observed in wild-derived strains relative to B6, including 19 genes previously associated with human AD including Apoe, Trem2, and Sorl1. This resource is critical in the development of appropriately targeted therapeutics for AD and other neurological diseases.
| S-EPMC7937391 | biostudies-literature
Project description:Experimental studies of neuroinflammation in Alzheimer's disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture human brain microglia in high purity for experimental studies were discussed. These methods were employed to isolate human microglia for investigation of a number of features of neuroinflammation, including activation phenotypes, neurotoxicity, responses to abnormal aggregated proteins such as amyloid beta, phagocytosis, and the effects of aging and disease on microglia cellular properties. In recent years, interest in human microglia and neuroinflammation has been renewed due to the identification of inflammation-related AD genetic risk factors, in particular the triggering receptor expressed on myeloid cells (TREM)-2. Because of the difficulties in developing effective treatments for AD, there has been a general need for greater understanding of the functions of microglia in normal and AD brains. While most experimental studies on neuroinflammation have employed rodent microglia, this review considered the role of human microglia in experimental studies. This review focused on the development of in vitro methodology for the culture of postmortem human microglia and the key findings obtained from experimental studies with these cells.
| S-EPMC6721636 | biostudies-literature