The Nucleotide-binding Leucine-rich Repeat (NLR) Family Member NLRX1 Mediates Protection against Experimental Autoimmune Encephalomyelitis and Represses Macrophage/Microglia-induced Inflammation

Eitas, Timothy K.; Chou, Wei-Chun; Wen, Haitao; Gris, Denis; Robbins, Gregory R.; Brickey, June; Oyama, Yoshitaka; Ting, Jenny P.-Y.

doi:10.1074/jbc.m113.533034

Cited by 47 publications

(49 citation statements)

References 32 publications

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“…To date, there have been very few studies evaluating NLRX1 function in the CNS. To our knowledge, the only prior in vivo study of NLRX1 in the CNS characterized its role in modulating experimental autoimmune encephalomyelitis (EAE)(62). EAE is a common autoimmune mouse model of multiple sclerosis and is associated with the loss of immunological tolerance to CNS-derived antigens.…”

Section: Discussionmentioning

confidence: 99%

“…EAE is a common autoimmune mouse model of multiple sclerosis and is associated with the loss of immunological tolerance to CNS-derived antigens. In the EAE model, NLRX1 was found to play a robust protective role (62). Nlrx1 −/− mice were shown to have significantly increased clinical parameters associated with disease progression and corresponding increases in tissue damage during EAE (62).…”

Section: Discussionmentioning

confidence: 99%

“…In the EAE model, NLRX1 was found to play a robust protective role (62). Nlrx1 −/− mice were shown to have significantly increased clinical parameters associated with disease progression and corresponding increases in tissue damage during EAE (62). The Nlrx1 −/− animals were also more susceptible to myelin-reactive T cells following adoptive transfer (62).…”

Section: Discussionmentioning

confidence: 99%

“…Nlrx1 −/− mice were shown to have significantly increased clinical parameters associated with disease progression and corresponding increases in tissue damage during EAE (62). The Nlrx1 −/− animals were also more susceptible to myelin-reactive T cells following adoptive transfer (62). The mechanism associated with NLRX1 protection in the EAE model was further associated with the attenuation of macrophage and microglia activation (62).…”

Section: Discussionmentioning

confidence: 99%

“…The Nlrx1 −/− animals were also more susceptible to myelin-reactive T cells following adoptive transfer (62). The mechanism associated with NLRX1 protection in the EAE model was further associated with the attenuation of macrophage and microglia activation (62). Indeed, microglia and macrophages cultured from Nlrx1 −/− mice have been previously shown to generate excessive amounts of various pro-inflammatory cytokines, including IL-6 and CCL2, following PAMP stimulation (10, 11, 15, 62).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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Role of Innate Genes in HIV Replication

Schott

Rieß

König

2017

Roles of Host Gene and Non-Coding RNA Expression in Virus Infection

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Cells use an elaborate innate immune surveillance and defense system against virus infections. Here, we discuss recent studies that reveal how HIV-1 is sensed by the innate immune system. Furthermore, we present mechanisms on the counteraction of HIV-1. We will provide an overview how HIV-1 actively utilizes host cellular factors to avoid sensing. Additionally, we will summarize effectors of the innate response that provide an antiviral cellular state. HIV-1 has evolved passive mechanism to avoid restriction and to regulate the innate response. We review in detail two prominent examples of these cellular factors: (i) NLRX1, a negative regulator of the innate response that HIV-1 actively usurps to block cytosolic innate sensing; (ii) SAMHD1, a restriction factor blocking the virus at the reverse transcription step that HIV-1 passively avoids to escape sensing.

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Pharmacological inhibition of soluble epoxide hydrolase attenuates chronic experimental autoimmune encephalomyelitis by modulating inflammatory and anti-inflammatory pathways in an inflammasome-dependent and -independent manner

et al. 2020

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The Nucleotide-binding Leucine-rich Repeat (NLR) Family Member NLRX1 Mediates Protection against Experimental Autoimmune Encephalomyelitis and Represses Macrophage/Microglia-induced Inflammation

Cited by 47 publications

References 32 publications

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

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

Role of Innate Genes in HIV Replication

Pharmacological inhibition of soluble epoxide hydrolase attenuates chronic experimental autoimmune encephalomyelitis by modulating inflammatory and anti-inflammatory pathways in an inflammasome-dependent and -independent manner

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