title: Human IL10 gene repression by Rev-erbα ameliorates Mycobacterium tuberculosis clearance.
abstract: Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erbα 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-erbα in monocytes and macrophages. The nuclear localization of Rev-erbα in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erbα elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erbα overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erbα 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-erbα bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.
authors: Department of Protein Science and Molecular Biology, Institute of Microbial Technology/Council of Scientific and Industrial Research (CSIR), Sector 39 A, Chandigarh 160036, India.
authors: Vemika
authors: V
authors: Chandra
authors: Sahil
authors: S
authors: Mahajan
authors: Ankita
authors: A
authors: Saini
authors: Hedwin K
authors: HK
authors: Dkhar
authors: Ravikanth
authors: R
authors: Nanduri
authors: Ella B
authors: EB
authors: Raj
authors: Ashwani
authors: A
authors: Kumar
authors: Pawan
authors: P
authors: Gupta
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000378:metabolism*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020218:Response Elements; D013045:Species Specificity; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C508609:IL10 protein, human; C556062:IL10 protein, mouse; C064353:NR1D1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D016753:Interleukin-10