Interleukin-10 Alters Effector Functions of Multiple Genes Induced by Borrelia burgdorferi in Macrophages To Regulate Lyme Disease Inflammation

Gautam, Aarti; Dixit, Saurabh; Philipp, Mario T.; Singh, Shree R.; Morici, Lisa A.; Kaushal, Deepak; Dennis, Vida A.

doi:10.1128/iai.05451-11

Cited by 52 publications

(63 citation statements)

References 99 publications

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“…Similar observations have been made in microglial cells, where the pro-or anti-inflammatory states have been elicited by different cytokines or bacterial components (4). In this context, gene expression profiling studies of murine macrophages and microglial cells have identified immunoresponsive gene 1 (Irg1) as one of the most highly up-regulated genes under proinflammatory conditions, such as bacterial infections (5)(6)(7)(8)(9). Increased Irg1 expression levels have also been detected in chicken spleen macrophages after infection with Salmonella enterica (10).…”

mentioning

confidence: 54%

Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

Michelucci

Cordes

Ghelfi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

903

922

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Immunoresponsive gene 1 (Irg1) is highly expressed in mammalian macrophages during inflammation, but its biological function has not yet been elucidated. Here, we identify Irg1 as the gene coding for an enzyme producing itaconic acid (also known as methylenesuccinic acid) through the decarboxylation of cis-aconitate, a tricarboxylic acid cycle intermediate. Using a gain-and-loss-of-function approach in both mouse and human immune cells, we found Irg1 expression levels correlating with the amounts of itaconic acid, a metabolite previously proposed to have an antimicrobial effect. We purified IRG1 protein and identified its cis-aconitate decarboxylating activity in an enzymatic assay. Itaconic acid is an organic compound that inhibits isocitrate lyase, the key enzyme of the glyoxylate shunt, a pathway essential for bacterial growth under specific conditions. Here we show that itaconic acid inhibits the growth of bacteria expressing isocitrate lyase, such as Salmonella enterica and Mycobacterium tuberculosis. Furthermore, Irg1 gene silencing in macrophages resulted in significantly decreased intracellular itaconic acid levels as well as significantly reduced antimicrobial activity during bacterial infections. Taken together, our results demonstrate that IRG1 links cellular metabolism with immune defense by catalyzing itaconic acid production.

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mentioning

confidence: 54%

Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

Michelucci

Cordes

Ghelfi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

903

922

View full text Add to dashboard Cite

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“…qRT-PCR was employed to quantify mRNA gene transcripts of various inflammatory genes using the TaqMan ® RNA-to-C T TM 1-step kit in combination with TaqMan ® gene expression assays (Applied Biosystems-Life Technologies, Carlsbad, CA, USA) as reported. 38 Amplification of gene transcripts was performed according to the manufacturer's protocol using ABI ViiA™ 7 real time PCR (Applied Biosystems) and standard amplification conditions. The relative changes in gene expression were calculated using the equation: 2 −ΔΔCT where all values were normalized with respect to the "housekeeping" gene GAPDH (glyceraldehyde 3-phosphate dehydrogenase) mRNA levels.…”

Section: Rna Extraction and Quantitative Real Time Polymerase Chain Rmentioning

confidence: 99%

Anti-inflammatory effects of silver-polyvinyl pyrrolidone (Ag-PVP) nanoparticles in mouse macrophages infected with live Chlamydia trachomatis

Yilma¹,

Singh²,

Dixit³

et al. 2013

IJN

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Abstract:Chlamydia trachomatis is a very common sexually transmissible infection in both developing and developed countries. A hallmark of C. trachomatis infection is the induction of severe inflammatory responses which play critical roles in its pathogenesis. Antibiotics are the only treatment option currently available for controlling C. trachomatis infection; however, they are efficacious only when administered early after an infection. The objectives of this study are to explore alternative strategies in the control and regulation of inflammatory responses triggered by a C. trachomatis infection. We employed silver-polyvinyl pyrrolidone (Ag-PVP) nanoparticles, which have been shown to possess anti-inflammatory properties, as our target and the in vitro mouse J774 macrophage model of C. trachomatis infection. Our hypothesis is that small sizes of Ag-PVP nanoparticles will control inflammatory mediators triggered by a C. trachomatis infection. Cytotoxicity studies using Ag-PVP nanoparticles of 10, 20, and 80 nm sizes revealed .80% macrophage viability up to a concentration of 6.25 µg/mL, with the 10 nm size being the least toxic. All sizes of Ag-PVP nanoparticles, especially the 10 nm size, reduced the levels of the prototypic cytokines, tumor necrosis factor (TNF) and interleukin (IL)-6, as elicited from C. trachomatis infected macrophages. Additionally, Ag-PVP nanoparticles (10 nm) selectively inhibited a broad spectrum of other cytokines and chemokines produced by infected macrophages. Of significance, Ag-PVP nanoparticles (10 nm

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“…A recent study identified immune response gene 1 (IRG1) as a critical player linking metabolism to innate immunity in oxidative stress response (37). IRG1 was originally identified as a highly inducible gene in murine macrophages following lipopolysaccharide stimulation (38) and is upregulated by proinflammatory cytokines and by viral and bacterial infections (39)(40)(41)(42)(43)(44)(45). The IRG1 gene is highly conserved among different species.…”

mentioning

confidence: 99%

Suppression of IRG-1 Reduces Inflammatory Cell Infiltration and Lung Injury in Respiratory Syncytial Virus Infection by Reducing Production of Reactive Oxygen Species

Ren

Zhuo

et al. 2016

J Virol

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Respiratory syncytial virus (RSV) infection is a common cause of lower respiratory tract illness in infants and children. RSV is a negative-sense, single-strand RNA (ssRNA) virus that mainly infects airway epithelial cells. Accumulating evidence indicates that reactive oxygen species (ROS) production is a major factor for pulmonary inflammation and tissue damage of RSV disease. We investigated immune-responsive gene-1 (IRG1) expression during RSV infection, since IRG1 has been shown to mediate innate immune response to intracellular bacterial pathogens by modulating ROS and itaconic acid production. We found that RSV infection induced IRG1 expression in human A549 cells and in the lung tissues of RSV-infected mice. RSV infection or IRG1 overexpression promoted ROS production. Accordingly, knockdown of IRG1 induction blocked RSV-induced ROS production and proinflammatory cytokine gene expression. Finally, we showed that suppression of IRG1 induction reduced immune cell infiltration and prevented lung injury in RSV-infected mice. These results therefore link IRG1 induction to ROS production and immune lung injury after RSV infection. IMPORTANCERSV infection is among the most common causes of childhood diseases. Recent studies identify ROS production as a factor contributing to RSV disease. We investigated the cause of ROS production and identified IRG1 as a critical factor linking ROS production to immune lung injury after RSV infection. We found that IRG1 was induced in A549 alveolar epithelial cells and in mouse lungs after RSV infection. Importantly, suppression of IRG1 induction reduced inflammatory cell infiltration and lung injury in mice. This study links IRG1 induction to oxidative damage and RSV disease. It also uncovers a potential therapeutic target in reducing RSV-caused lung injury. Human infection with respiratory syncytial virus (RSV) is a major cause of childhood disease of lower respiratory tract infection with common cold-like symptoms. The infection is frequently associated with the development of bronchospasm and bronchiolitis, particularly in children less than 1 year old. Globally, RSV is responsible for over 33 million new episodes of acute lower respiratory tract infection in children, with at least 3.4 million severe cases that require hospital admissions each year (1, 2). A growing body of evidence shows that RSV infection has become a significant burden in the elderly in industrialized countries (3-6). In addition, RSV infection may contribute to the onset of development of type 2 diabetes (7). Proinflammatory response in the lung is thought to play a fundamental role in RSV disease, but the mechanisms regulating RSV disease and long-term consequences are incompletely defined (8-13).RSV is a negative-sense, single-strand RNA virus of the family Paramyxoviridae, which also includes common respiratory viruses such as those causing measles and mumps. Human RSV infects polarized epithelial cells in the airway and, to lesser degrees, macrophages and dendritic cells (14,15). RSV stimul...

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Interleukin-10 Alters Effector Functions of Multiple Genes Induced by Borrelia burgdorferi in Macrophages To Regulate Lyme Disease Inflammation

Abstract: Interleukin-10 (IL-10) modulates inflammatory responses elicited in vitro and in vivo by

Cited by 52 publications

References 99 publications

Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production

Anti-inflammatory effects of silver-polyvinyl pyrrolidone (Ag-PVP) nanoparticles in mouse macrophages infected with live Chlamydia trachomatis

Suppression of IRG-1 Reduces Inflammatory Cell Infiltration and Lung Injury in Respiratory Syncytial Virus Infection by Reducing Production of Reactive Oxygen Species

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