NLRP3: A promising therapeutic target for autoimmune diseases

Shen, Hui‐Hui; Yang, Yuexin; Meng, Xiang; Luo, Xiaoyun; Li, Xiaomei; Shuai, Zongwen; Ye, Dong‐Qing; Pan, Hai‐Feng

doi:10.1016/j.autrev.2018.01.020

Cited by 219 publications

(137 citation statements)

References 126 publications

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“…There has been increasing attention on the molecular mechanisms of NLRP3 in a number of diseases. Recent studies have reported significant protective effects resulting from suppression of NLRP3 inflammasome activation in liver fibrosis, systemic sclerosis, systemic lupus erythematosus, systemic sclerosis, diabetes, inflammasome-related eye disease, inflammatory bowel disease, rheumatoid arthritis, and CNS diseases (Zhou et al, 2016;Alegre et al, 2017;Rovira-Llopis et al, 2018;Shen et al, 2018;Yerramothu et al, 2018;Chen et al, 2019a). Meng et al (2019) demonstrated that PPARγ activation exerts an anti-inflammatory effect by suppressing NLRP3 inflammasome activation in spinal cord-derived neurons.…”

Section: Discussionmentioning

confidence: 99%

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Jiao

Zhao

Wang

et al. 2020

Front. Mol. Biosci.

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Spinal cord injury (SCI) is a serious condition that affects bodily function; however, there is no effective therapy in clinical practice. MCC950, a selective NOD-like receptor protein-3 (NLRP3) inflammasome inhibitor, has been reported to alleviate canonical and non-canonical NLRP3 inflammasome activation of the inflammatory response in vitro and in vivo. However, the effect of MCC950 treatment on neurological post-SCI recovery remains unclear. In this study, we assessed the pharmacological effect of MCC950 on an experimental SCI model in vivo and neuronal injury in vitro. We found that MCC950 improved the grip strength, hind limb movements, spinal cord edema, and pathological injury in the SCI mice. We demonstrated that it exerted this effect by blocking NLRP3 inflammasome assembly, including NLRP3-ASC and NLRP3-Caspase-1 complexes, as well as the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-18. Moreover, we found that MCC950 reduced spinal neuron injury and NLRP3 inflammasome activation, which had been induced by oxygen-glucose deprivation (OGD) or lipopolysaccharides (LPS) in vitro. In conclusion, our findings indicate that MCC950 alleviates inflammatory response and improves functional recovery in the acute mice model of SCI by blocking NLRP3 inflammasome assembly and alleviating downstream neuroinflammation. Therefore, these findings could prove useful in the development of effective therapeutic strategies for the treatment and prognosis of SCI.

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Section: Discussionmentioning

confidence: 99%

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Jiao

Zhao

Wang

et al. 2020

Front. Mol. Biosci.

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“…In many autoimmune and inflammatory diseases, such as SLE and RA, high serum titers of IL-18 correlate with onset and/or severity of disease (11). Also, IL-18 is a product of the NLRP3 inflammasome and numerous studies have connected activation of this inflammatory machinery with autoimmune disease as well as obesity-driven inflammation (34). However, in vivo administration of IL-18 alone in wild-type mice has been shown to induce IgG1 and IgE antibody production and this response depended on CD4 + T cells (35).…”

Section: Discussionmentioning

confidence: 99%

Combined proinflammatory cytokine and cognate activation of invariant natural killer T cells enhances anti-DNA antibody responses

Sedimbi

Hägglöf

Garimella

et al. 2020

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

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Invariant natural killer T (iNKT) cells serve as early rapid responders in the innate immune response to self-derived autoantigens and pathogen-derived danger signals and antigens. iNKT cells can serve both as helpers for effector B cells and negatively regulate autoreactive B cells. Specifically, iNKT cells drive B cell proliferation, class switch, and antibody production to induce primary antigen-specific immune responses. On the other hand, inflammasome-mediated activation drives accumulation of neutrophils, which license iNKT cells to negatively regulate autoreactive B cells via Fas ligand (FasL). This positions iNKT cells at an apex to support or inhibit B cell responses in inflammation. However, it is unknown which effector mechanism dominates in the face of cognate glycolipid activation during chronic inflammation, as might result from glycolipid vaccination or infection during chronic autoimmune disease. We stimulated iNKT cells by cognate glycolipid antigen α-galactosylceramide (αGalCer) and measured B cell activation during interleukin 18 (IL-18)-induced chronic inflammation. Moreover, glycolipid-activated iNKT cells increased the serum concentration of autoantibodies, frequency of germinal center (GC) B cells, and antigen-specific plasma cells induced during chronic IL-18–mediated inflammation, as compared with IL-18 alone. Further, activation of iNKT cells via cognate glycolipid during IL-18–mediated inflammation overrides the licensing function of neutrophils, instead inducing iNKT follicular helper (iNKTfh) cells that in turn promote autoimmunity. Thus, our data demonstrate that glycolipids which engage iNKT cells support antigen-specific B cell help during inflammasome-mediated inflammation.

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“…The inflammatory process, a protective response against various infectious and sterile noxious stimuli, is responsible for the elimination of the stressor agent resulting in a return to tissue homeostasis (1,2). However, continuous inflammation is associated with persistent harmful stimuli or failed inflammatory resolution (3)(4)(5). The resolution of inflammation is a wellcontrolled process resulting in a reduction of leukocyte accumulation and an increase in neutrophil apoptosis, macrophages reprogramming, and functional recovery of tissue.…”

Section: Introductionmentioning

confidence: 99%

Sensory Ganglia-Specific TNF Expression Is Associated With Persistent Nociception After Resolution of Inflammation

et al. 2020

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systemic injection of etanercept, an agent clinically utilized for TNF neutralization, at day 7 post arthritis induction, alleviated the persistent joint hyperalgesia by specific action in DRG. Our data suggest that neuroinflammation in DRG after the resolution of acute joint inflammation drives continuous neural sensitization resulting in persistent joint nociception in a TNF-dependent mechanism.

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NLRP3: A promising therapeutic target for autoimmune diseases

Cited by 219 publications

References 126 publications

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Combined proinflammatory cytokine and cognate activation of invariant natural killer T cells enhances anti-DNA antibody responses

Sensory Ganglia-Specific TNF Expression Is Associated With Persistent Nociception After Resolution of Inflammation

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