MEF2C mediates the activation induced cell death (AICD) of macrophages

Fu, Wenxia; Wei, Junnian; Gu, Jun

doi:10.1038/sj.cr.7310073

Cited by 15 publications

(10 citation statements)

References 32 publications

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“…Importantly, up-regulation of transcripts associated with immunoregulation in the BBDR rat did not occur; instead we observed opposite temporal regulation during progression to T1D in the analysis of the human subject. Genes that were not up-regulated included Hopx; Lgals1 , which encodes the immunoregulatory glycan-binding protein galectin-1 that in turn acts as a suppressive agent for T-cell responses 41 ; the transcription factor Mef2c that promotes activation mediated cell death of macrophages 42 ; Cbl , a negative regulator of immune receptor signal transduction; the inhibitory immunoreceptor Pilra 43 and others (Figure 7B). Conversely, among transcripts reduced over time in the BBDR profile 0, we observed an opposite pattern in the human T1D subject.…”

Section: Resultsmentioning

confidence: 99%

Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes

et al. 2013

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The dilute plasma cytokine milieu associated with Type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease-associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after immunological perturbation in young animals. After weaning, the BBDR temporal signature showed early coincident induction of transcription related to innate inflammation as well as IL-10- and TGF-β-mediated regulation. BBDR plasma cytokine levels mirrored the signatures showing early inflammation, followed by induction of a regulated state that correlated with failure of virus to induce T1D in older rats. In contrast, the BBDR.lyp/lyp temporal signature exhibited asynchronous dynamics, with delayed induction of inflammatory transcription and later, weaker induction of regulatory transcription, consistent with their deficiency in regulatory T cells. Through longitudinal analyses of plasma induced signatures in BB rats and a human T1D progressor, we have identified changes in immunoregulatory processes that attenuate a preexisting innate inflammatory state in BBDR rats, suggesting a mechanism underlying the decline in T1D susceptibility with age.

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Section: Resultsmentioning

confidence: 99%

Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes

et al. 2013

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“…The importance of Abcd transporters is reinforced by decreased transcript levels of other Abcd family members during Brucella infection (9, 77). Lastly, the alteration of mef2c expression suggests that B. neotomae infection may render RAW 264.7 macrophages more susceptible to activation-induced cell death (78) than B. melitensis or B. ovis infections. When compared to B. melitensis and B. ovis , B. neotomae infected macrophages appeared to have decreased immuno-stimulatory capability resulting in reduced oxidative stress and increased susceptibility to cell death.…”

Section: Discussionmentioning

confidence: 99%

Brucella melitensis, B. neotomaeandB. ovisElicit Common and Distinctive Macrophage Defense Transcriptional Responses

Covert

Mathison

Eskra

et al. 2009

Exp Biol Med (Maywood)

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Brucella spp. establish an intracellular replicative niche in macrophages, while macrophages attempt to eliminate the bacteria by innate defense mechanisms. Brucella spp. possess similar genomes yet exhibit different macrophage infections. Few B. melitensis and B. neotomae enter macrophages with intracellular adaptation occurring over 4-8 hr. Conversely, B. ovis are readily ingested by macrophages and exhibit a persistent plateau of infection. Evaluating early macrophage interaction with Brucella spp. allows discovery of host entry and intracellular translocation mechanisms. Microarray analysis of macrophage transcriptional response following a 4 hr infection by different Brucella spp. revealed common macrophage genes altered in expression compared to uninfected macrophages. Macrophage infection with three different Brucella spp. provokes a common innate immune theme with increased transcript levels of chemokines and defense response genes and decreased transcript levels of GTPase signaling and cytoskeletal function that may affect trafficking of Brucella containing vesicles. For example, transcript levels of genes associated with chemotaxis (IL-1β, MIP-1α), cytokine regulation (Socs3) and defense (Fas, Tnf) were increased, while transcript levels of genes associated with vesicular trafficking (Rab3d) and lysosomal associated enzymes (prosaposin) were decreased. Genes with altered macrophage transcript levels among Brucella spp. infections may correlate with species specific host defenses and intracellular survival strategies. Depending on the infecting Brucella species, gene ontology categorization identified genes differentially involved in cell growth and maintenance, endopeptidase inhibitor activity and Gprotein mediated signaling. Examples of decreased gene expression in B. melitensis infection but not other Brucella spp. were growth arrest (Gas2), immunoglobulin receptor (FcγrI) and chemokine receptor (Cxcr4) genes, suggesting opposing effects on intracellular functions.

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“…The elimination of hyperactivated monocytes could represent a process that is capable of downtuning cross-activation between autoreactive T cells and myeloid cells in the context of autoimmune reactions, which may be an important function during the attenuation of autoimmune diseases. AICD of T cells is an important mechanism for maintaining self-tolerance, but AICD of monocytes has been neglected to date [17][18][19]. However, there is a tight regulation balancing survival versus death signals of monocytes [20][21][22].…”

Section: Discussionmentioning

confidence: 99%

Activation‐dependent cell death of human monocytes is a novel mechanism of fine‐tuning inflammation and autoimmunity

et al. 2016

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In patients with juvenile idiopathic arthritis (JIA), increased release of IFN-γ and GM-CSF in cells infiltrating synovial tissue can be a potent driver of monocyte activation. Given the fundamental role of monocyte activation in remodeling the early phases of inflammatory responses, here we analyze the GM-CSF/IFN-γ induced activity of human monocytesin such a situation in vitro and in vivo. Monocytes from healthy donors were isolated and stimulated with GM-CSF ± IFN-γ. Monocyte activation and death were analyzed by flow cytometry, immunofluorescence microscopy, ELISA, and qPCR. T-cell GM-CSF/IFN-γ expression and monocyte function were determined in synovial fluid and peripheral blood from 15 patients with active JIA and 21 healthy controls. Simultaneous treatment with GM-CSF and IFN-γ induces cell death of monocytes. This cell death is partly cathepsin B-associated and has morphological characteristics of necrosis. Monocytes responding to costimulation with strong proinflammatory activities are consequently eliminated. Monocytes surviving this form of hyperactivation retain normal cytokine production. Cathepsin B activity is increased in monocytes isolated from synovial fluid from patients with active arthritis. Our data suggest GM-CSF/IFN-γ induced cell death of monocytes as a novel mechanism to eliminate overactivated monocytes, thereby potentially balancing inflammation and autoimmunity in JIA.Keywords: Arthritis · Autoimmunity · Caspase · Host defense ·Immune activation · Immune response Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Jan Däbritz e-mail: Jan.Daebritz@med.uni-rostock.de IntroductionThe pathogenesis of autoimmune joint diseases including juvenile idiopathic arthritis (JIA) involves a complex interplay of aberrantly activated innate and adaptive immune cells. In this context, C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1998 Jan Däbritz et al. Eur. J. Immunol. 2016. 46: 1997 T cells are an important source of cytokines such as interferon gamma (IFN-γ). More recently, the importance of interleukin (IL)-23 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing T-helper (Th) 17 cells for autoimmunity has been established [1,2]. GM-CSF production by T cells has been linked to several autoimmune inflammatory diseases, including multiple sclerosis (MS), myocarditis, and arthritis [3]. The precise mechanism by which GM-CSF promotes autoimmunity has not been described, but the existing literature identifies GM-CSF as a key cytokine by which Th17 cells might activate myeloid cells, thereby linking the adaptive with the innate immune system in autoimmunity [4]. These data were generated in mouse models and their relation to the human system is not fully established, but notably an enrichment of IFN-γ/GM-CSF coproducing cells within the Th17 population in the inflamed joints of children with JIA has recently been demonstrated [5,6]. Both IFN-γ and GM-CSF are potent inducers of mono...

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MEF2C mediates the activation induced cell death (AICD) of macrophages

Cited by 15 publications

References 32 publications

Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes

Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes

Brucella melitensis, B. neotomaeandB. ovisElicit Common and Distinctive Macrophage Defense Transcriptional Responses

Activation‐dependent cell death of human monocytes is a novel mechanism of fine‐tuning inflammation and autoimmunity

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