IFN-γ, a soluble cytokine being produced by T lymphocytes, macrophages, mucosal epithelial cells, or natural killer cells, is able to bind to the IFN-γ receptor (IFNγR) and in turn activate the Janus ...kinase (JAK)-signal transducer and transcription protein (STAT) pathway and induce expression of IFN-γ-stimulated genes. IFN-γ is critical for innate and adaptive immunity and aberrant IFN-γ expression and functions have been associated with different human diseases. However, the IFN-γ/IFNγR signaling could be a double-edged sword in cancer development because the tissue microenvironments could determine its anti- or pro-tumorigenic activities. The IFNγR protein consists of two IFNγR1 and IFNγR2 chains, subunits of which play different roles under certain conditions. This review assessed IFNγR polymorphisms, expression and functions in development and progression of various human diseases in an IFN-γ-dependent or independent manner. This review also discussed tumor microenvironment, microbial infection, and vital molecules in the IFN-γ upstream signaling that might regulate IFNγR expression, drug resistance, and druggable strategy, to provide evidence for further application of IFNγR.
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•IFN-γ/IFNγR signaling is a double-edged sword in the development of human diseases.•IFNγR1 and IFNγR2 play different roles in an IFN-γ-dependent or independent manner.•IFN-γR polymorphism, expression and functions are associated with different diseases.•IFN-γ upstream signaling regulates IFNγR, tumor development and druggable strategy.•We explore IFNγR1/2-related actions to provide evidence for further IFNγR application.
Auraptene as member of dietary coumarins, is found in citrus fruits. Former studies have demonstrated its anti-inflammatory and anti-cancer activity.
The mechanism of action and immune-modulatory ...property of this compound on human lymphocytes are greatly unknown.
The effect of three concentrations (10, 30 and 90 µM) of auraptene or dexamethasone (0.1 mM) were evaluated on percentage of cell proliferation and nitric oxide (NO) production as well as secretion and gene expression of cytokines, and NF-κB level in PHA-stimulated and non-stimulated lymphocytes.
In non-stimulated cells, all three concentrations of auraptene significantly increased the gene expression index of IL-10 (P < 0.05–0.001). The IFN-γ gene expression index, IFN-γ/IL-4 and IL-10/IL-4 gene expression ratio were significantly increased due to the high concentration (90 µM) of auraptene treatment compared to control group (P < 0.05–0.001). In PHA stimulation, all three concentrations of the extract significantly decreased proliferation, cytokines (IL-4, IL-10 and IFN-γ) and NF-κB level as well as NO production, but IFN-γ/IL-4 and IL-10/IL-4 ratio were significantly increased compared control group (P < 0.05–0.001). Gene expression of IL-10 and IL-4 was decreased but that of IFN-γ as well as FN-γ/IL-4 and IL-10/IL-4 ratio were significantly increased due to all three concentrations of auraptene.
The results showed promoting effects of auraptene on T cell subsets toward Th1 (IFN-γ) and Treg (IL-10), which suggest its therapeutic value for treatment of Th2 cells predominant diseases including allergic disease such as asthma and atopic dermatitis as well as cancers.
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration and demyelination in the central nervous system (CNS). IFN‐gamma (IFN‐γ), a critically important ...immunomodulator, has been widely studied in MS pathology. The confusing and complex effects of IFN‐γ in MS patients and rodent models, however, cause us to look more closely at its exact role in MS. In this study, we identified the role of the IFN‐γ signaling in the choroid plexus (CP) in the experimental autoimmune encephalomyelitis (EAE) model. We found that the IFN‐γ signal was rapidly amplified when CNS immune cell infiltration occurred in the CP during the progressive stage. Furthermore, using two CP‐specific knockdown strategies, we demonstrated that blocking the IFN‐γ signal via knockdown of IFN‐γR1 in the CP could protect mice against EAE pathology, as evidenced by improvements in clinical scores and infiltration. Notably, knocking down IFN‐γR1 in the CP reduced the local expression of adhesion molecules and chemokines. This finding suggests that IFN‐γ signaling in the CP may participate in the pathological process of EAE by preventing pathological T helper (Th) 17+ cells from infiltrating into the CNS. Finally, we showed that the unbalanced state of IFN‐γ signaling between peripheral lymphocytes and the choroid plexus may determine whether IFN‐γ has a protective or aggravating effect on EAE pathology. Above all, we discovered that IFN‐γR1‐mediated IFN‐γ signaling in the CP was a vital pathway in the pathological process of EAE.
We identified the role of the IFN‐γ signaling in the choroid plexus (CP) in the experimental autoimmune encephalomyelitis (EAE) model. We found that the IFN‐γ signal was rapidly amplified when CNS immune cell infiltration occurred in the CP during the progressive stage. With CP‐specific knockdown strategy, we demonstrated that blocking the IFN‐γR1 signal in the CP could protect mice against EAE pathology, as evidenced by improvement in clinical scores and infiltration of T cells.
Tumor immunoediting consisting of three phases of elimination, equilibrium or dormancy, and escape has been supported by preclinical and clinical data. A comprehensive understanding of the molecular ...mechanisms by which antitumor immune responses regulate these three phases are important for developing highly tailored immunotherapeutics that can control cancer. To this end, IFN‐γ produced by Th1 cells, cytotoxic T cells, NK cells, and NKT cells is a pleiotropic cytokine that is involved in all three phases of tumor immunoediting, as well as during inflammation‐mediated tumorigenesis processes. This essay presents a review of literature and suggests that overcoming tumor escape is feasible by driving tumor cells into a state of quiescent but not indolent dormancy in order for IFN‐γ‐producing tumor‐specific T cells to prevent tumor relapse.
Review on the mechanisms by which IFN‐gamma manifests paradoxical functions of relevance to developing highly tailored immunotherapeutics for cancer patients.
Mesenchymal stem cells (MSCs) have been approved as a cellular drug for the treatment of a variety of immune‐related diseases by the government of many countries'. Previous investigations, including ...ours, have shown that exosomes secreted by MSCs (MSC‐ex) are one of the main factors responsible for the therapeutic effect of MSCs. However, the immune modulation activities and the contents of MSC‐ex derived from cells under different incubation conditions differ dramatically. Therefore, the optimal way to ensure effectiveness is by identifying and preparing MSC‐ex with confirmed potent immunosuppressive activity. The aim of this study was to investigate and analyze the composition and function of MSC‐ex secreted by MSCs stimulated by different cytokines to obtain exosomes with more potent immunosuppressive activity. To achieve this aim, umbilical cord‐derived MSCs were treated with PBS, TGF‐β, IFN‐γ, or TGF‐β plus IFN‐γ for 72 hr. Then, exosomes were isolated from the culture supernatants. Common exosome markers, such as CD9, CD63, and CD81, were detected and analyzed by FCM. At the same time, the TGF‐β, IFN‐γ, IDO, and IL‐10 content in exosomes was detected, and the influence of exosmes from defferent groups on the induction of mononuclear cell transformation into Tregs was analyzed via FCM. Our results show that the TGF‐β combined with IFN‐γ exosome group more effectively promoted the transformation of mononuclear cells to Tregs, and the analysis showed that IDO may play an important role. This study might provide a novel strategy to treat GVHD as well as other immune‐associated disorders.
MSC‐ex secreted by MSCs stimulated with cytokines of TGF‐βplus IFN‐γcan promote PBMCs to differentiate into Tregs, which may be related with a variety of increasing cytokines, and IDO plays an important role in the process.
Granuloma annulare (GA) is an idiopathic condition characterized by granulomatous inflammation in the skin. Prior studies have suggested that GA develops from various triggers, leading to a complex ...interplay involving innate and adaptive immunity, tissue remodeling, and fibrosis. Macrophages are the major immune cells comprising GA granulomas; however, the molecular drivers and inflammatory signaling cascade behind macrophage activation are poorly understood. Histologically, GA exhibits both palisaded and interstitial patterns on histology; however, the molecular composition of GA at the spatial level remains unexplored. GA is a condition without Food and Drug Administration–approved therapies despite the significant impact of GA on QOL. Spatial transcriptomics is a valuable tool for profiling localized, genome-wide gene expression changes across tissues, with emerging applications in clinical medicine. To improve our understanding of the spatially localized gene expression patterns underlying GA, we profiled the spatial gene expression landscape from 6 patients with GA. Our findings revealed mixed T helper 1 and T helper 2 signals comprising the GA microenvironment and spatially distinct M1 and M2 macrophage polarization characteristics. IFN-γ and TNF signals emerged as important regulators of GA granulomatous inflammation, and IL-32 emerged as a key driver of granulomatous inflammation. Overall, our spatial transcriptomics data indicate that GA exhibits mixed immune and macrophage polarization.
CD8+ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and ...immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune‐resistance. Cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8
+ T cell‐mediated antitumor immune responses. Thus, CD8
+ T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8
+ T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4
+ T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so‐called infiltrated–inflamed I–I TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8
+ T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death‐1 receptor (PD‐1)–ligand (PD‐L1) and CTL‐associated antigen 4 (CTLA‐4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8
+ T cells and renewing their priming, respectively, and thereby eliminating antigen‐expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells.
Tumors have specific mechanisms to break T cell responses. CD8+ T cells are the key immune cells for killing cancer cells presenting major histocompatibility complex (MHC) class I molecules. For pursuing this purpose, the cells must first be primed by their cardinal interactions with dendritic cells (DCs), natural killer (NK) cells, and CD4
+ T cells, among them play essential roles for this priming. Then, the primed cells are activated to form effector cytotoxic T lymphocytes (CTLs) for killing cancer cells via release of granules or induction of FasL‐mediated apoptosis. In the established tumors, however, the function of these key effector cells is suppressed by immunosuppressive cross‐talking between cancer cells with tumor stromal cells like cancer‐associated fibroblasts (CAFs), regulatory T cells (Tregs), and macrophage type 2 (M2) cells. CTL‐based therapy can distract cancer cells, and the density of CD8
+ T cells infiltrated to the invasive site of tumor is a predictive marker for influencing the outcomes of immune checkpoint blockade (ICB) blockade therapy. It is suggested to use a combination of immunotherapeutic approaches for rescuing the exhausted CTLs and switching them toward their active effector profile for retaining immunoactivation within the tumor microenvironment (TME) for combatting tumors and enhancing the efficacy of chemo or radiotherapeutic approaches.
Neuroinflammation driven by interferon‐gamma (IFN‐γ) and microglial activation has been linked to neurological disease. However, the effects of IFN‐γ‐activated microglia on hippocampal neurogenesis ...and behavior are unclear. In the present study, IFN‐γ was administered to mice via intracerebroventricular injection. Mice received intraperitoneal injection of ruxolitinib to inhibit the JAK/STAT1 pathway or injection of minocycline to inhibit microglial activation. During a 7‐day period, mice were assessed for depressive‐like behaviors and cognitive impairment based on a series of behavioral analyses. Effects of the activated microglia on neural stem/precursor cells (NSPCs) were examined, as was pro‐inflammatory cytokine expression by activated microglia. We showed that IFN‐γ‐injected animals showed long‐term adult hippocampal neurogenesis reduction, behavior despair, anhedonia, and cognitive impairment. Chronic activation with IFN‐γ induces reactive phenotypes in microglia associated with morphological changes, population expansion, MHC II and CD68 up‐regulation, and pro‐inflammatory cytokine (IL‐1β, TNF‐α, IL‐6) and nitric oxide (NO) release. Microglia isolated from the hippocampus of IFN‐γ‐injected mice suppressed NSPCs proliferation and stimulated apoptosis of immature neurons. Inhibiting of the JAK/STAT1 pathway in IFN‐γ‐injected animals to block microglial activation suppressed microglia‐mediated neuroinflammation and neurogenic injury, and alleviated depressive‐like behaviors and cognitive impairment. Collectively, these findings suggested that priming of microglia with IFN‐γ impairs adult hippocampal neurogenesis and leads to depression‐like behaviors and cognitive defects. Targeting microglia by modulating levels of IFN‐γ the brain may be a therapeutic strategy for neurodegenerative diseases and psychiatric disorders.
Main Points
IFN‐γ induces microglial activation through the JAK/STAT pathway.
Priming of microglia with IFN‐γ impairs immature neurons and adult hippocampal neurogenesis.
Priming of microglia with IFN‐γ leads to depression‐like behaviors and cognitive defects.
Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN‐γ immunity. Since 1996, disease‐causing mutations have been found in 11 genes, which, through allelic ...heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase‐like 2 A deficiency, (2) TYK2‐deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN‐γR2 deficiency, and (4) two forms of syndromic MSMD: RORγ/RORγT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.
Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN‐γ immunity. Since 1996, disease‐causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014.
Reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia in AD pathogenesis is still unclear. Here, using metabolic profiling, we found ...that exposure to amyloid-β triggers acute microglial inflammation accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis. It was dependent on the mTOR-HIF-1α pathway. However, once activated, microglia reached a chronic tolerant phase as a result of broad defects in energy metabolisms and subsequently diminished immune responses, including cytokine secretion and phagocytosis. Using genome-wide RNA sequencing and multiphoton microscopy techniques, we further identified metabolically defective microglia in 5XFAD mice, an AD mouse model. Finally, we showed that metabolic boosting with recombinant interferon-γ treatment reversed the defective glycolytic metabolism and inflammatory functions of microglia, thereby mitigating the AD pathology of 5XFAD mice. Collectively, metabolic reprogramming is crucial for microglial functions in AD, and modulating metabolism might be a new therapeutic strategy for AD.
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•Aβ induces metabolic reprogramming of microglia from OXPHOS to glycolysis•Metabolic reprogramming of microglia is dependent on the mTOR-HIF-1α pathway•Chronic exposure to Aβ induces metabolic defects of microglia•Metabolic boosting with IFN-γ restores immunological function of microglia
Baik et al. report that amyloid-β acutely triggers microglial activation and metabolic reprogramming from OXPHOS to glycolysis. However, chronic exposure to amyloid-β induces overall metabolic defects in microglia in a model of Alzheimer's disease. Treatment with IFN-γ restores glycolytic metabolism and immunological function of microglia, suggesting that modulation of microglial metabolism may be a potential therapeutic strategy.
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