Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Abstract

Background: Transcriptional modulation of IL10, a cytokine that blocks phagolysosome maturation, is not well understood. Results: This study demonstrates human IL10 gene repression by direct binding of Rev-erb␣ on Rev-DR2 in the proximal promoter. Conclusion: Rev-erb␣ binds to IL10 proximal promoter, represses expression, and impedes Mycobacterium tuberculosis in human macrophages. Significance: This study provides rationale to target Rev-erb␣ as a therapeutic intervention that might support host defense in tuberculosis.Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erb␣ is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erb␣ in monocytes and macrophages. The nuclear localization of Rev-erb␣ in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erb␣ elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erb␣ overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erb␣ binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erb␣ bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.Macrophages are immune system sentinels with a major role to play in both innate and adaptive immunity. They are the key effectors in antimicrobial defense, atherogenesis, autoimmunity, and many other inflammatory diseases (1). Although the activation, function, classification, and plasticity of these cells have been studied extensively with regard to cellular signaling, the cytokine environment, and surface, cellular, or secretory markers, studies of the underlying molecular mechanism have mostly addressed NF-B (2). Similarly, modulation of macrophage function and alteration of disease pathology by small molecules such as heme, lipids, or drugs such as rifampicin are well understood at the translational level of the effectors (3, 4), but the transcriptional mechanism involving interactions of these ligands with transcriptional molecules and the resulting expression patterns have not been investigated.This study focuses on Rev-erb␣, an adopted orphan nuclear receptor that belongs to the steroid/thyroid hormone receptor superfamily and is a known ...

Mycobacterium tuberculosisKeto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair

“…Our recent work along with other reports has shown that PPARg and TR4 provoke the anti-inflammatory and pro-M. tuberculosis properties of macrophages (28,32,34). In addition, different groups have also reported other nuclear receptors such as vitamin D receptors, Rev-erba, and LXRa anti-infectives functions against M. tuberculosis (27,28,(61)(62)(63)(64)(65).…”

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

“…Conclusion-Many of the key studies supporting a role for heme in recruiting NCoR1 to Rev-erb NRs are based on experiments with the ␣-isoform (16,21,34,86,109), which is more extensively studied, likely because of its discovery prior to Reverb␤ and its unique context in the genome being transcribed on the opposite strand of the gene coding for THR␣ on chromosome 17 (2, 9), whereas Rev-erb␤ is encoded on chromosome 3. Because the DBD and LBD of the two receptors share a high level of homology and nearly identical heme binding properties (9,36), it has been assumed that the mechanism of heme regulation would be the same for both isoforms.…”

NR1D1 amelioratesMycobacterium tuberculosisclearance through regulation of autophagy

“…[5][6][7][8][9] Our recent report establishes its role in ameliorating Mycobacterium tuberculosis clearance by direct repression of the human IL10 gene. 10 Recent reports, including our study on the role of NR1D1 in infection and inflammation, suggest that NR1D1 behaves as an equilibrist whereby it finetunes the regulatory pathways in order to maintain the equilibrium in cellular processes. [10][11][12] Many proteins are involved in the expulsion of bacterium from the host.…”

“…10 Recent reports, including our study on the role of NR1D1 in infection and inflammation, suggest that NR1D1 behaves as an equilibrist whereby it finetunes the regulatory pathways in order to maintain the equilibrium in cellular processes. [10][11][12] Many proteins are involved in the expulsion of bacterium from the host. These include CLEC7A/dectin-1, TLRs (toll-like receptors), dendritic cell-specific CD209/DC-SIGN, soluble Ctype lectins such as SFTPA (surfactant protein A), SFTPD and MBL (mannose-binding lectin), VDR (vitamin D [1,25-dihydroxyvitamin D3] receptor), and NR1H/LXR.…”