scholarly journals Transcription cofactor GRIP1 differentially affects myeloid cell–driven neuroinflammation and response to IFN-β therapy

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Sanda Mimouna ◽  
David A. Rollins ◽  
Gayathri Shibu ◽  
Bowranigan Tharmalingam ◽  
Dinesh K. Deochand ◽  
...  
Keyword(s):  
Immune Cell ◽  
Myeloid Cell ◽  
Type I ◽  
Type I Ifn ◽  
Autoimmune Encephalomyelitis ◽  
Interacting Protein ◽  
Transcription Cofactor ◽  
Experimental Autoimmune ◽  
Permissive Role

Macrophages (MФ) and microglia (MG) are critical in the pathogenesis of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Glucocorticoids (GCs) and interferon β (IFN-β) are frontline treatments for MS, and disrupting each pathway in mice aggravates EAE. Glucocorticoid receptor–interacting protein 1 (GRIP1) facilitates both GR and type I IFN transcriptional actions; hence, we evaluated the role of GRIP1 in neuroinflammation. Surprisingly, myeloid cell–specific loss of GRIP1 dramatically reduced EAE severity, immune cell infiltration of the CNS, and MG activation and demyelination specifically during the neuroinflammatory phase of the disease, yet also blunted therapeutic properties of IFN-β. MФ/MG transcriptome analyses at the bulk and single-cell levels revealed that GRIP1 deletion attenuated nuclear receptor, inflammatory and, interestingly, type I IFN pathways and promoted the persistence of a homeostatic MG signature. Together, these results uncover the multifaceted function of type I IFN in MS/EAE pathogenesis and therapy, and an unexpectedly permissive role of myeloid cell GRIP1 in neuroinflammation.

scholarly journals Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

2018 ◽  
Vol 115 (20) ◽  
pp. 5253-5258 ◽  
Author(s):  
Hideyuki Yanai ◽  
Shiho Chiba ◽  
Sho Hangai ◽  
Kohei Kometani ◽  
Asuka Inoue ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Gene Ablation ◽  
Cell Type Specific

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4–IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

scholarly journals Impaired Development of CD4+ CD25+ Regulatory T Cells in the Absence of STAT1

2003 ◽  
Vol 199 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Takeaki Nishibori ◽  
Yoshinari Tanabe ◽  
Leon Su ◽  
Michael David
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Regulatory T Cells ◽  
Cell Receptor ◽  
Type I ◽  
Autoimmune Encephalomyelitis ◽  
Self Tolerance ◽  
Opposing Effects ◽  
Experimental Autoimmune

Type I and II interferons (IFNs) exert opposing effects on the progression of multiple sclerosis, even though both IFNs use the signal transducer and activator of transcription 1 (STAT1) as a signaling mediator. Here we report that STAT1-deficient mice expressing a transgenic T cell receptor against myelin basic protein spontaneously develop experimental autoimmune encephalomyelitis with dramatically increased frequency. The heightened susceptibility to this autoimmune disease appears to be triggered by a reduced number as well as a functional impairment of the CD4+ CD25+ regulatory T cells in STAT1-deficient animals. Adoptive transfer of wild-type regulatory T cells into STAT1-deficient hosts is sufficient to prevent the development of autoimmune disease. These results demonstrate an essential role of STAT1 in the maintenance of immunological self-tolerance.

The role of microglial activation in disease progression

2014 ◽  
Vol 20 (10) ◽  
pp. 1288-1295 ◽  
Author(s):  
Jorge Correale
Keyword(s):  
Microglial Activation ◽  
Proteolytic Enzymes ◽  
Myeloid Cell ◽  
Autoimmune Encephalomyelitis ◽  
Unique Type ◽  
Central Nervous System Damage ◽  
Progressive Neurodegeneration ◽  
And Function ◽  
Experimental Autoimmune

Microglia, a unique type of myeloid cell, play a key role in the inflammation-mediated neurodegeneration occurring during both acute and chronic stages of multiple sclerosis (MS). These highly specialized cells trigger neurotoxic pathways, producing pro-inflammatory cytokines, reactive oxygen and nitrogen species and proteolytic enzymes, causing progressive neurodegeneration. Microglia have also been associated with development of cortical lesions in progressive MS, as well as with alterations of synaptic transmission in experimental autoimmune encephalomyelitis (EAE). However, they also play an important role in the promotion of neuroprotection, downregulation of inflammation, and stimulation of tissue repair. Notably, microglia undergo changes in morphology and function with normal aging, resulting in a decline of their ability to repair central nervous system damage, making axons and neurons more vulnerable with age. Modulation of microglial activation for therapeutic purposes must consider suppressing deleterious effects of these cells, while simultaneously preserving their protective functions.

scholarly journals Central Nervous System-Endogenous TLR7 and TLR9 Induce Different Immune Responses and Effects on Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 15 ◽  
Author(s):  
Ruthe Storgaard Dieu ◽  
Vian Wais ◽  
Michael Zaucha Sørensen ◽  
Joanna Marczynska ◽  
Magdalena Dubik ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Protective Role ◽  
Type I ◽  
Type I Ifn ◽  
Autoimmune Encephalomyelitis ◽  
Tlr9 Signaling ◽  
Experimental Autoimmune

Innate receptors, including Toll like receptors (TLRs), are implicated in pathogenesis of CNS inflammatory diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). TLR response to pathogens or endogenous signals includes production of immunoregulatory mediators. One of these, interferon (IFN)β, a Type I IFN, plays a protective role in MS and EAE. We have previously shown that intrathecal administration of selected TLR ligands induced IFNβ and infiltration of blood-derived myeloid cells into the central nervous system (CNS), and suppressed EAE in mice. We have now extended these studies to evaluate a potential therapeutic role for CNS-endogenous TLR7 and TLR9. Intrathecal application of Imiquimod (TLR7 ligand) or CpG oligonucleotide (TLR9 ligand) into CNS of otherwise unmanipulated mice induced IFNβ expression, with greater magnitude in response to CpG. CD45+ cells in the meninges were identified as source of IFNβ. Intrathecal CpG induced infiltration of monocytes, neutrophils, CD4+ T cells and NK cells whereas Imiquimod did not recruit blood-derived CD45+ cells. CpG, but not Imiquimod, had a beneficial effect on EAE, when given at time of disease onset. This therapeutic effect of CpG on EAE was not seen in mice lacking the Type I IFN receptor. In mice with EAE treated with CpG, the proportion of monocytes was significantly increased in the CNS. Infiltrating cells were predominantly localized to spinal cord meninges and demyelination was significantly reduced compared to non-treated mice with EAE. Our findings show that TLR7 and TLR9 signaling induce distinct inflammatory responses in the CNS with different outcome in EAE and point to recruitment of blood-derived cells and IFNβ induction as possible mechanistic links between TLR9 stimulation and amelioration of EAE. The protective role of TLR9 signaling in the CNS may have application in treatment of diseases such as MS.

scholarly journals Sex-Specific Effects of Microglia-Like Cell Engraftment During Experimental Autoimmune Encephalomyelitis

2020 ◽  
Author(s):  
Jinming Han ◽  
Keying Zhu ◽  
Kai Zhou ◽  
Ramil Hakim ◽  
Sreenivasa Raghavan Sankavaram ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Clinical Symptoms ◽  
Myeloid Cell ◽  
Active Immunization ◽  
Inflammatory Factors ◽  
Male Mice ◽  
Autoimmune Encephalomyelitis ◽  
Peripheral Monocyte ◽  
Experimental Autoimmune

Abstract BackgroundMultiple Sclerosis (MS) is a chronic neuroinflammatory disorder of the central nervous system (CNS) that usually presents in young adults and predominantly in females. Microglia, a major resident immune cell in the CNS, are critical players in both CNS homeostasis and disease. We have previously demonstrated that microglia can be efficiently depleted by the administration of tamoxifen in Cx3cr1CreER/+Rosa26DTA/+ mice, with ensuing repopulation deriving from both the proliferation of residual CNS resident microglia and the engraftment of peripheral monocyte-derived microglia-like cells. MethodsTamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ and Cx3cr1CreER/+ female and male mice. Experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, was induced by active immunization with myelin oligodendrocyte glycoprotein one month after tamoxifen injections in Cx3cr1CreER/+Rosa26DTA/+ mice and Cx3cr1CreER/+ mice, a time point when the CNS niche was colonized by microglia derived from both CNS microglia and peripherally-derived macrophages. CNS myeloid cell compositions during acute and chronic EAE were measured by flow cytometry.ResultsWe demonstrate that engraftment of microglia-like cells following microglial depletion exacerbated EAE in Cx3cr1CreER/+Rosa26DTA/+ female mice as assessed by clinical symptoms and the expression of CNS inflammatory factors, but these findings were not evident in male mice. Higher major histocompatibility complex class II expression and cytokine production in the female CNS contributed to the sex-dependent EAE severity in mice following engraftment of microglia-like cells. ConclusionThe engraftment of microglia-like cells following microglial depletion exacerbated EAE in females. An underestimated yet marked sex-dependent microglial activation pattern may exist in the injured CNS during EAE.

scholarly journals SLAMF9 regulates pDC homeostasis and function in health and disease

2019 ◽  
Vol 116 (33) ◽  
pp. 16489-16496 ◽  
Author(s):  
Lital Sever ◽  
Lihi Radomir ◽  
Kristin Stirm ◽  
Anna Wiener ◽  
Nofar Schottlender ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Adaptive Immune Response ◽  
Response Analysis ◽  
Type I ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Health And Disease ◽  
And Function ◽  
Experimental Autoimmune

SLAMF9 belongs to the conserved lymphocytic activation molecule family (SLAMF). Unlike other SLAMs, which have been extensively studied, the role of SLAMF9 in the immune system remained mostly unexplored. By generating CRISPR/Cas9 SLAMF9 knockout mice, we analyzed the role of this receptor in plasmacytoid dendritic cells (pDCs), which preferentially express the SLAMF9 transcript and protein. These cells display a unique capacity to produce type I IFN and bridge between innate and adaptive immune response. Analysis of pDCs in SLAMF9−/− mice revealed an increase of immature pDCs in the bone marrow and enhanced accumulation of pDCs in the lymph nodes. In the periphery, SLAMF9 deficiency resulted in lower levels of the transcription factor SpiB, elevation of pDC survival, and attenuated IFN-α and TNF-α production. To define the role of SLAMF9 during inflammation, pDCs lacking SLAMF9 were followed during induced experimental autoimmune encephalomyelitis. SLAMF9−/− mice demonstrated attenuated disease and delayed onset, accompanied by a prominent increase of immature pDCs in the lymph node, with a reduced costimulatory potential and enhanced infiltration of pDCs into the central nervous system. These results suggest the crucial role of SLAMF9 in pDC differentiation, homeostasis, and function in the steady state and during experimental autoimmune encephalomyelitis.

PS1-011. The Role Of Type I Interferon Signaling Via T Cells In The Early Phase Of Experimental Autoimmune Encephalomyelitis (EAE)

Cytokine ◽  
2011 ◽  
Vol 56 (1) ◽  
pp. 18-19
Author(s):  
Nadia Kavrochorianou ◽  
Maria Evangelidou ◽  
Michael Tovey ◽  
George Thyphronitis ◽  
Sylva Haralambous
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Early Phase ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

scholarly journals Role of the Innate Immunity Signaling Pathway in the Pathogenesis of Sjögren’s Syndrome

2021 ◽  
Vol 22 (6) ◽  
pp. 3090
Author(s):  
Toshimasa Shimizu ◽  
Hideki Nakamura ◽  
Atsushi Kawakami
Keyword(s):  
Immune Responses ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.

Sign in / Sign up

Export Citation Format

Share Document