The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells

Lukens, John R.; Gurung, Prajwal; Shaw, Patrick J.; Barr, Maggie; Zaki, Hasan; Brown, Scott A.; Vogel, Peter; Chi, Hongbo; Kanneganti, Thirumala‐Devi

doi:10.1016/j.immuni.2015.03.006

Cited by 99 publications

(140 citation statements)

References 48 publications

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“…Indeed, studies utilizing both human clinical samples and/or mouse models have shown a role for these unique proteins in the modulation of neuroinflammation (48, 49). To date, the vast majority of studies have focused on inflammasome forming NLRs in mice and their contribution to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (49–51).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…These proinflammatory NLRs are counterbalanced by other NLRs and other molecules that regulate inflammasome activity. These include anti-inflammatory NLRs include NLRC3, NLRP6, NLRP12, NLRX1 and transactivators of MHC II molecules such as CIITA (Lukens et al, 2015; Moore et al, 2008; Parvatiyar and Cheng, 2011). The complexity of the inflammasome highlights the importance of negative feedback loops, in which some members of the inflammasome promote inflammation and others reduce inflammation.…”

Section: Introductionmentioning

confidence: 99%

Rapid Inflammasome Activation following Mucosal SIV Infection of Rhesus Monkeys

Barouch

Ghneim

Bosche

et al. 2016

Cell

120

128

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The earliest events following mucosal HIV-1 infection, prior to measurable viremia, remain poorly understood. Here we show by detailed necropsy studies that the virus can disseminate rapidly following mucosal SIV infection of rhesus monkeys and trigger components of the inflammasome, both at the site of inoculation and at early sites of distal virus spread. By 24 hours following inoculation, a proinflammatory signature that lacked antiviral restriction factors was observed in viral RNA positive tissues. The early innate response included expression of NLRX1, which inhibits antiviral responses, and activation of the TGF-β pathway, which negatively regulates adaptive immune responses. These data suggest a model in which the virus triggers specific host mechanisms that suppress the generation of antiviral innate and adaptive immune responses in the first few days of infection, thus facilitating its own replication. These findings have important implications for the development of vaccines and other strategies to prevent infection.

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“…20B e C). (BRUCHARD et al, 2015;LUKENS et al, 2015;ZAKI et al, 2011), podendo ser alvos terapêuticos no controle de doenças autoimunes ou inflamatórias.…”

Section: Nlrp12 -/-unclassified

“…Além disso, outro fato interessante é que o inflamassoma Nlrp12 tem sido descrito como um modulador negativo da resposta inflamatória, uma vez que animais deficientes para esse receptor possuem aumento da fosforilação do NF-κB (ALLEN et al, 2012;LICH et al, 2007;LUKENS et al, 2015;WANG et al, 2002;WILLIAMS et al, 2005 (ARTHUR et al, 2010;ZAMOSHNIKOVA et al, 2015).…”

Section: Nlrp12 -/-unclassified

“…Sabendo que as células Th17 são cruciais no desenvolvimento de doenças autoimunes, como a artrite reumatoide, pelo aumento da infiltração de neutrófilos, diferenciação de osteoclastos e destruição da cartilagem (BETTELLI; OUKKA; KUCHROO, 2007;HIROTA et al, 2007;LANGRISH, 2005;LUBBERTS, 2015;LUBBERTS et al, 2004) o direcionamento para a resposta Th17 (LUKENS et al, 2015).…”

Section: Nlrp12 -/-unclassified

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Participação do <i>Nlrp12</i> na diferenciação de linfócitos Th17 e no desenvolvimento da artrite experimental

Prado¹

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AGRADECIMENTOSAos meus pais Geova e Clarice, pela educação, incentivo e por me ensinarem a importância da família na formação pessoal. Muito obrigado por tudo e desculpa por esse tempo longe. Vocês são os melhores pais do mundo.Aos meus irmãos Lindaura, Giliard, Rafael e Cíntia, pela amizade e por sempre estarem dispostos a me ajudar, amo vocês.Ao Prof. Dr. José Carlos Farias Alves Filho, pela paciência, por ter me aceitado no grupo e pela orientação.Aos professores Fernando e Thiago Cunha, por terem ajudado no desenvolvimento desse projeto.Aos professores Dario e Niels por terem aceitado o convite de participar da minha banca examinadora em um período que não é muito agradável. Nlrp12 é regulado positivamente durante o desenvolvimento da artrite experimental, sendo um modulador negativo desse processo. Isso se deve a uma redução na resposta inflamatória inata do modelo e pela modulação negativa na resposta Th17. Nesse sentido, o controle da resposta Th17 e o desenvolvimento da artrite experimental ocorre por um mecanismo dependente da fosforilação do fator de transcrição Stat3, que é crítico na diferenciação de linfócitos Th17. Desta forma, este estudo demonstra uma nova função para o sensor Nlrp12 no desenvolvimento da artrite experimental, por modular a resposta imune adaptativa de forma direta nos linfócitos T CD4.Palavras-Chaves: Nlrp12, Linfócitos Th17, Artrite e Stat3. Thus, Nlrp12 downregulates innate inflammatory response from experimental model and Th17 response. Therefore, experimental arthritis development and Th17 differentiation control occurs in a Stat3 phosphorylation dependente-manne, which is a critical transcription factor on Th17 differentiation. Thus, this study demonstrates a new function for Nlrp12 on experimental arthritis development, by directly to modulate adaptive immune response in CD4 cells.

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The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells

Cited by 99 publications

References 48 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

Rapid Inflammasome Activation following Mucosal SIV Infection of Rhesus Monkeys

Participação do <i>Nlrp12</i> na diferenciação de linfócitos Th17 e no desenvolvimento da artrite experimental

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