Suppression of NLRX1 in chronic obstructive pulmonary disease

Kang, Min Jong; Yoon, Chang Min; Kim, Bo Hye; Lee, Chang Min; Zhou, Yang; Sauler, Maor; Homer, Robert J.; Dhamija, Anish; Boffa, Daniel J.; West, A. Phillip; Shadel, Gerald S.; Tedrow, John; Kaminski, Naftali; Kim, Woo Jin; Lee, Chang-Min; Oh, Yeon Mok; Elias, Jack A.

doi:10.1172/jci71747

Cited by 68 publications

(71 citation statements)

References 13 publications

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“…TUFM has been described as interacting with the mitochondria-localized, nucleotidebinding, leucine-rich repeats (NLRX1) gene to reduce cytokine response and augment virus-induced autophagy (68,69). In a recent study, three independent cohorts of patients with COPD were demonstrated to have decreased levels of NLRX1 mRNA, which was associated with increased disease severity, decreased pulmonary function, poorer quality of life, and worse prognosis (70). The TUFM and NLRX1 relationship, together with the association between variants in the 16p11.2 region and TUFM expression levels, and evidence for differential TUFM expression in COPD tissue provide support for a potential role of TUFM and more generally lend biologic plausibility to the association between COPD susceptibility and the 16p11.2 locus containing rs181206.…”

Section: Discussionmentioning

confidence: 99%

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Hobbs

Parker²,

Chen

et al. 2016

Am J Respir Crit Care Med

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Rationale: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.Objectives: To identify coding variants associated with COPD.Methods: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.Measurements and Main Results: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 3 10 214 ) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 3 10 26 ) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 3 10 28 ) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. Conclusions:In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Hobbs

Parker²,

Chen

et al. 2016

Am J Respir Crit Care Med

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“…NLRX1 has been best characterized in the context of pathogen recognition (13, 15, 16). However, recent studies have extended the function of NLRX1 beyond this initial role in modulating host-pathogen interactions and identified contributions to cancer, chronic obstructive pulmonary disease, inflammatory bowel disease, and the modulation of cell death (11, 17–19). …”

Section: Introductionmentioning

confidence: 99%

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

Theus

Brickler

Meza

et al. 2017

The Journal of Immunology

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Traumatic and non-traumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity and free radical release contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we utilized Nlrx1−/− mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). Here, we show that the Nlrx1−/− mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. Mechanistically, our data indicate that the NF-κB signaling cascade is significantly up-regulated in the Nlrx1−/− animals. This up-regulation is associated with increased microglia and macrophage populations in the cortical lesion. Utilizing a mouse neuroblastoma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-κB signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host-pathogen defense and identify this highly novel NLR as a significant modulator of brain injury progression.

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“…For example, COPD is a pulmonary disorder characterized by chronic inflammation and aberrant tissue remodeling in response to cigarette smoke exposure and other external stimuli. Studies have shown mitochondrial dysfunction in patients with COPD and have implicated several mitochondrial related genes such as MAVS and NLRX1 in its pathogenesis (Kang and Shadel, 2016; Kang et al, 2015; Yoon et al, 2016). …”

Section: Recent Advances – Mitochondrial Dysfunction/damps and Cmentioning

confidence: 99%

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

2018

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Inflammation represents a comprehensive host response to external stimuli for the purpose of eliminating the offending agent, minimizing injury to host tissues and fostering repair of damaged tissues back to homeostatic levels. In normal physiologic context, inflammatory response culminates with the resolution of infection and tissue damage response. However, in a pathologic context, persistent or inappropriately regulated inflammation occurs that can lead to chronic inflammatory diseases. Recent scientific advances have integrated the role of innate immune response to be an important arm of the inflammatory process. Accordingly, the dysregulation of innate immunity has been increasingly recognized as a driving force of chronic inflammatory diseases. Mitochondria have recently emerged as organelles which govern fundamental cellular functions including cell proliferation or differentiation, cell death, metabolism and cellular signaling that are important in innate immunity and inflammation-mediated diseases. As a natural consequence, mitochondrial dysfunction has been highlighted in a myriad of chronic inflammatory diseases. Moreover, the similarities between mitochondrial and bacterial constituents highlight the intrinsic links in the innate immune mechanisms that control chronic inflammation in diseases where mitochondrial damage associated molecular patterns (DAMPs) have been involved. Here in this review, the role of mitochondria in innate immune responses is discussed and how it pertains to the mitochondrial dysfunction or DAMPs seen in chronic inflammatory diseases is reviewed.

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Suppression of NLRX1 in chronic obstructive pulmonary disease

Cited by 68 publications

References 13 publications

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-κB Signaling following Brain Injury

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

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