Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis

Mahajan, Sahil; Saini, Ankita; Chandra, Vemika; Nanduri, Ravikanth; Kalra, Rashi; Bhagyaraj, Ella; Khatri, Neeraj; Gupta, Pawan

doi:10.1074/jbc.m115.638064

Cited by 68 publications

(60 citation statements)

References 52 publications

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“…Macrophage Infection and Determination of Colony-forming Units (cfu)-As described previously, peritoneal macrophages and monocyte-derived macrophages (MDMs) were used as primary cell lines for intracellular infection (36,37), and THP-1 and RAW 264.7 macrophages were used as secondary cell lines. These cell lines were infected with either wild-type or recombinant strains of M. smegmatis expressing LprI, HbN, and LprIHbN at a multiplicity of infection of 1:5 for 2 h. For the intracellular survival assay in the presence of lysozyme, 100 g/ml HEWL was exogenously supplemented at the time of infection.…”

Section: Bacterial Strains and Growth Conditions-recombinantmentioning

confidence: 99%

Lipoprotein LprI of Mycobacterium tuberculosis Acts as a Lysozyme Inhibitor

Sethi¹,

Mahajan²,

Singh

et al. 2016

Journal of Biological Chemistry

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Mycobacterium tuberculosis, the causative agent of tuberculosis, is one of the most dreaded human pathogens that affect millions of lives worldwide (1). The inexplicable success of M. tuberculosis as a human pathogen relies on its ability to utilize a number of defense strategies to adapt its metabolism in response to a plethora of environmental challenges during the course of its pathogenic cycle (2, 3). Several of the components of its protein machinery have emerged as virulence factors with vital implications. Among these, lipoproteins play pivotal roles in several functions related to its virulence and host-pathogen interactions (4 -6). Genome analysis of mycobacteria indicated that the number of lipoproteins is much higher in the pathogenic mycobacteria in comparison with their non-pathogenic counterparts, and M. tuberculosis houses the highest number of lipoproteins.LprI is a novel lipoprotein that is exclusively present in pathogenic mycobacteria belonging to M. tuberculosis complex. The genomic location of the lprI gene is conserved among pathogenic mycobacteria where it has been identified as an operon partner of the glbN gene, which encodes truncated hemoglobin (HbN) 3 (7,8). The lprI gene is positioned adjacent to the glbN gene, separated through an intergenic distance of 58 nucleotides, and their co-transcription has been observed in Mycobacterium bovis (9), indicating that these two proteins may have functional correlation. The HbN of M. tuberculosis carries potent nitric oxide (NO) detoxification ability (8 -10) and is post-translationally modified by a glycan linkage that facilitates adherence and phagocytosis of cells during macrophage infection (11). The functional relevance of the co-occurrence of LprI with HbN in M. tuberculosis is unknown. Similar co-existence of a lipoprotein, LprG, along with Rv1410, which encodes a small molecule transporter, P55 (an operon conserved in M. tuberculosis complex), has also been observed in M. tuberculosis (12) where they function in a cooperative and synchronized manner. Because the HbN of M. tuberculosis plays a vital role in and is also involved in modulating host-pathogen interactions during intracellular infection of M. tuberculosis, it is likely that the glbN-lprI operon may also have some significant implications in the physiology of tubercle bacillus. LprI is an uncharacterized lipoprotein of M. tuberculosis complex; therefore, in the absence of any knowledge on LprI, its physiological function and implications of its co-existence with the HbN in M. tuberculosis are difficult to understand. To investigate the crucial implications of HbN in modulating the host-pathogen interactions and immune system of the host by providing aid in the better survival and sustenance of M. tuberculosis during intracellular infection, it is important to study the functionality of the LprI to understand functional implications of their co-occurrence in M. tuberculosis.In silico analysis unraveled that LprI carries a lysozyme-binding motif of the membrane-bound lysozyme in...

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Section: Bacterial Strains and Growth Conditions-recombinantmentioning

confidence: 99%

Lipoprotein LprI of Mycobacterium tuberculosis Acts as a Lysozyme Inhibitor

Sethi¹,

Mahajan²,

Singh

et al. 2016

Journal of Biological Chemistry

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“…Stars indicate P<0.05. and Src inhibitors may suppress PI3K and STAT3 along with ERK. NR4A2 is known to be regulated by PI3K-Akt signaling whose simultaneous suppression with ERK may significantly impact NR4A2 regulation (24).…”

Section: Discussionmentioning

confidence: 99%

Drug screening to target nuclear orphan receptor NR4A2 for cancer therapeutics

Komiya

Yamamoto

Roy³

et al. 2017

Transl. Lung Cancer Res.

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“…cPLA 2 ␣ activation and prostaglandin production serve to dampen inflammation by modulating the transcriptional response through cAMP, as exemplified by the induction of the immunosuppressive cytokine IL10 and suppression of TNF␣ production (24). The transcription factor NR4A2, which is rapidly induced in C. albicans-infected cPLA 2 ␣ ϩ/ϩ but not in cPLA 2 ␣ Ϫ/Ϫ RPM, has been shown to play a role in dampening inflammation (77,78). The feedback regulation of COX-2 expression by prostaglandins through increases in cAMP is well documented, but there are cell-specific differences in mechanisms of induction (32,52).…”

Section: Discussionmentioning

confidence: 99%