Krüppel-like factor 4, a novel transcription factor regulates microglial activation and subsequent neuroinflammation

Kaushik, Deepak; Gupta, Malvika; Das, Sulagna; Basu, Anirban

doi:10.1186/1742-2094-7-68

Cited by 90 publications

(112 citation statements)

References 65 publications

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“…Similar results were found with 2 commercial antibodies. A similar expression pattern of KLF4 in both the nucleus and cytoplasm has been reported in other tissues (22,23). It has been suggested that KLF4 is stored in the cytoplasm and translocates to the nucleus after stimulation (23), which would explain why both nuclear and cytoplasmic staining were observed.…”

Section: Discussionsupporting

confidence: 77%

KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria

Hayashi¹,

Sasamura²,

Nakamura³

et al. 2014

J. Clin. Invest.

102

117

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The transcription factor Kruppel-like factor 4 (KLF4) has the ability, along with other factors, to reprogram somatic cells into induced pluripotent stem (iPS) cells. Here, we determined that KLF4 is expressed in kidney glomerular podocytes and is decreased in both animal models and humans exhibiting a proteinuric. Transient restoration of KLF4 expression in podocytes of diseased glomeruli in vivo, either by gene transfer or transgenic expression, resulted in a sustained increase in nephrin expression and a decrease in albuminuria. In mice harboring podocyte-specific deletion of Klf4, adriamycin-induced proteinuria was substantially exacerbated, although these animals displayed minimal phenotypical changes prior to adriamycin administration. KLF4 overexpression in cultured human podocytes increased expression of nephrin and other epithelial markers and reduced mesenchymal gene expression. DNA methylation profiling and bisulfite genomic sequencing revealed that KLF4 expression reduced methylation at the nephrin promoter and the promoters of other epithelial markers; however, methylation was increased at the promoters of genes encoding mesenchymal markers, suggesting selective epigenetic regulation of podocyte gene expression. Together, these results suggest that KLF4 epigenetically modulates podocyte phenotype and function and that the podocyte epigenome can be targeted for direct intervention and reduction of proteinuria.

show abstract

Section: Discussionsupporting

confidence: 77%

KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria

Hayashi¹,

Sasamura²,

Nakamura³

et al. 2014

J. Clin. Invest.

102

117

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“…Our studies also provide insights regarding discrepant observations in the literature regarding the kinetics of KLF4 expression and its targets in response to proinflammatory stimuli. It is likely that (a) idiosyncrasies of various cell lines employed (e.g., J774a, THP-1, RAW, and BV-2) and (b) differences in the concentration (ranging from 10 ng/ml to 1,000 ng/ml) and source of LPS employed (e.g., E. coli, Porphyromonas gingivalis, and Salmonella enterica) may account for many of the disparate results seen among various studies (23)(24)(25)(26)(27)(28). For example, several studies in cell lines and/or primary cells have reported an increase in KLF4 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Our group and others have reported that KLF4 is expressed in a stage-specific pattern during myelopoiesis and functions to promote monocyte differentiation (21,22). While several studies have evaluated the role of KLF4 in macrophage cell lines (23)(24)(25)(26)(27)(28), the physiologic role of myeloid KLF4 in vivo has not been elucidated. Given the important roles of the KLF family members in cellular differentiation, we hypothesized that KLF4 might be involved in the transcriptional control of macrophage polarization.…”

Section: Introductionmentioning

confidence: 99%

Krüppel-like factor 4 regulates macrophage polarization

et al. 2011

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Current paradigms suggest that two macrophage subsets, termed M1 and M2, are involved in inflammation and host defense. While the distinct functions of M1 and M2 macrophages have been intensively studied -the former are considered proinflammatory and the latter antiinflammatory -the determinants of their speciation are incompletely understood. Here we report our studies that identify Krüppel-like factor 4 (KLF4) as a critical regulator of macrophage polarization. Macrophage KLF4 expression was robustly induced in M2 macrophages and strongly reduced in M1 macrophages, observations that were recapitulated in human inflammatory paradigms in vivo. Mechanistically, KLF4 was found to cooperate with Stat6 to induce an M2 genetic program and inhibit M1 targets via sequestration of coactivators required for NF-κB activation. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. Furthermore, mice bearing myeloid-specific deletion of KLF4 exhibited delayed wound healing and were predisposed to developing diet-induced obesity, glucose intolerance, and insulin resistance. Collectively, these data identify KLF4 as what we believe to be a novel regulator of macrophage polarization.

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“…The BV-2 cell line (a mouse microglia cell line) was provided by Steve Levison, University of Medicine and Dentistry, New Jersey, USA. BV-2 cells were grown at 37°C in Dulbecco's modified Eagle's medium (DMEM) supplemented with 5% sodium bicarbonate (NaHCO 3 ), 10% FBS, 100 U/ml penicillin, and 100 g/ml streptomycin, as described previously (25).…”

Section: Methodsmentioning

confidence: 99%

“…Primary microglia cells were isolated from BALB/c mouse pups of either sex (postnatal days 0 to 2), as reported previously (25). Briefly, the whole brain cortex was dissected from the mouse brain, and the meninges were removed under a dissecting microscope.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA 155 Regulates Japanese Encephalitis Virus-Induced Inflammatory Response by Targeting Src Homology 2-Containing Inositol Phosphatase 1

Thounaojam

Kundu

Kaushik

et al. 2014

J Virol

Self Cite

114

130

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MicroRNAs (miRNAs) are single-stranded small RNA molecules that regulate various cellular processes. miRNA 155 (miR-155) regulates various aspects of innate and adaptive immune responses and plays a key role in various viral infections and the resulting neuroinflammation. The present study evaluated the involvement of miR-155 in modulating Japanese encephalitis virus (JEV)-induced neuroinflammation. We observed that miR-155 expression was upregulated during JEV infection of mouse primary microglia, the BV-2 microglia cell line, and in both mouse and human brains. In vitro and in vivo knockdown of miR-155 minimized JEV-induced inflammatory responses. In the present study, we confirmed targeting of the Src homology 2-containing inositol phosphatase 1 (SHIP1) 3= untranslated region (UTR) by miR-155 in the context of JEV infection. Inhibition of SHIP1 by miR-155 resulted in higher beta interferon (IFN-␤) and proinflammatory cytokine production through activation of TANKbinding kinase 1 (TBK-1). Based on these observations, we conclude that miR-155 modulates the neuroinflammatory response during JEV infection via negative regulation of SHIP1 expression. Thus, modulation of miR-155 could be a novel strategy to regulate JEV-induced neuroinflammation. IMPORTANCE Japanese encephalitis virus (JEV), a member of the family Flaviviridae that causes Japanese encephalitis (JE), is the most common mosquito-borne encephalitis virus in the Japanese encephalitis virus (JEV), a member of the family Flaviviridae, is a single-stranded, positive-sense RNA virus that causes Japanese encephalitis (JE) (1, 2). JE is endemic in most Southeast Asian countries (3, 4). The availability of an effective vaccine and an active immunization program have resulted in a reduced number of JE cases in a few countries (5). The early clinical features of JE include fever, headache, and vomiting. Two weeks after JEV infection, patients develop neurological symptoms, like seizure, tremor, photophobia, and movement disorder (6). These clinical features are not exclusive to JEV infection, and hence, laboratory diagnosis is needed to differentiate it from other neurological disorders. Detection of anti-JEV IgM antibodies in the cerebrospinal fluid (CSF) and serum is frequently used to diagnose JE (7). The fatality rate of JEV infection is ϳ25%. A majority of survivors (ϳ50%) have neuropsychiatric sequelae; only ϳ25% recover completely (8). Hence, JEV poses major health concerns and economic burdens in the Asia-Pacific region. During the last decade, we and others have made significant progress in the understanding molecular mechanisms involved in JEV infection.MicroRNAs (miRNAs) are small, noncoding RNAs ϳ19 to 22 nucleotides in length that regulate various cellular processes by binding to the 3= untranslated region (UTR) of target proteins, resulting in either degradation of RNA or translational suppression (9, 10). Our knowledge of the role of miRNAs in various diseases is expanding rapidly. Various reports support the role of miRNAs in neuroviral...

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Krüppel-like factor 4, a novel transcription factor regulates microglial activation and subsequent neuroinflammation

Cited by 90 publications

References 65 publications

KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria

KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria

Krüppel-like factor 4 regulates macrophage polarization

MicroRNA 155 Regulates Japanese Encephalitis Virus-Induced Inflammatory Response by Targeting Src Homology 2-Containing Inositol Phosphatase 1

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