Interference of protein tyrosine phosphatase non-receptor type 22 inhibits NLRP3 inflammasome activation to alleviate inflammation after cerebral hemorrhage in rats

Lu WANG; Li ZHANG; Han XIAO; Hui GAN; Hui CHEN; Ning JIANG; Xuan ZHAI; Jing ZHAO; Yingliang LI

doi:10.16016/j.1000-5404.201907021

您当前的位置：

首页 >

文章列表页 >

Interference of protein tyrosine phosphatase non-receptor type 22 inhibits NLRP3 inflammasome activation to alleviate inflammation after cerebral hemorrhage in rats

Basic Medicine | 更新时间：2026-01-09

- Interference of protein tyrosine phosphatase non-receptor type 22 inhibits NLRP3 inflammasome activation to alleviate inflammation after cerebral hemorrhage in rats
- Journal of Third Military Medical University Vol. 41, Issue 24, Pages: 2409-2416(2019)
- 作者机构：
  
  1.400016 重庆, 重庆医科大学:附属儿童医院神经外科，儿童发育疾病研究教育部重点实验室，国家儿童健康与疾病临床医学研究中心，儿童发育重大疾病国家国际科技合作基地，儿科学重庆市重点实验室
  2.400016 重庆, 重庆医科大学:基础医学院
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81671158);the key project of Chonging Science and Technology Commission(2015jcyjBX0144)
- DOI：10.16016/j.1000-5404.201907021
  CLC： R345;R364.5;R743.34
- Received：03 July 2019，
  
  Revised：2019-08-15，
  
  Published：30 December 2019
- 稿件说明：
移动端阅览
Lu WANG, Li ZHANG, Han XIAO, et al. Interference of protein tyrosine phosphatase non-receptor type 22 inhibits NLRP3 inflammasome activation to alleviate inflammation after cerebral hemorrhage in rats[J]. Journal of Third Military Medical University, 2019, 41(24): 2409-2416.
DOI：

Lu WANG, Li ZHANG, Han XIAO, et al. Interference of protein tyrosine phosphatase non-receptor type 22 inhibits NLRP3 inflammasome activation to alleviate inflammation after cerebral hemorrhage in rats[J]. Journal of Third Military Medical University, 2019, 41(24): 2409-2416. DOI： 10.16016/j.1000-5404.201907021.

摘要

目的

探讨蛋白酪氨酸磷酸酶，非受体型22(protein tyrosine phosphatase non-receptor type 22

PTPN22)在大鼠脑出血后炎症反应中的作用及其机制。

方法

采用自体血注入脑内建立大鼠脑出血(intracerebral hemorrhage，ICH)模型，36只SD大鼠随机分为假手术组，ICH3、6、12、24、48 h组(

=6)，Western blot筛选大鼠脑出血后PTPN22表达的时间窗。72只大鼠随机分为假手术组、ICH组、ICH+NC组、ICH+PTPN22干扰组(

=18)。ICH24 h后，对各组大鼠进行神经功能评分(mNSS)，脑含水量测定，Western blot检测大鼠脑出血后血肿周围NLRP3，成熟的白介素-1β(cleaved-IL-1β)，成熟的白介素-18(cleaved-IL-18)以及激活的半胱天冬酶-1(cleaved-caspase-1)的表达，HE和Nissl染色观察大鼠脑组织形态学改变，免疫荧光染色检测血肿周围髓过氧化物酶(MPO)的表达。

结果

大鼠脑出血后12hPTPN22的表达开始升高，24 h达到峰值，48 h开始降低。差异具有统计学意义(

0.05)；与ICH+NC组相比，ICH+PTPN22干扰组神经功能评分降低，脑含水量减少，差异具有统计学意义(

0.05)；HE和Nissl染色结果可见，ICH+PTPN22干扰组脑组织损伤程度与ICH+NC组相比明显减轻；ICH+PTPN22干扰组大鼠脑出血后血肿周围NLRP3、cleaved-IL-1β、cleaved-IL-18以及cleaved-caspase-1的表达与ICH+NC组相比明显降低(

0.05)；ICH+PTPN22干扰组MPO细胞与ICH+NC组相比明显减少。

结论

干扰PTPN22可通过抑制NLRP3炎性体的激活从而减轻大鼠脑出血后的炎症损伤。

Abstract

Objective

To investigate the role of protein tyrosine phosphatase non-receptor type 22 (PTPN22) in inflammatory response following intracerebral hemorrhage (ICH) in rats and explore the mechanism that mediates its effect.

Methods

Rat models of ICH were established by injecting autologous blood into the brain of 30 SD rats

and Western blotting was performed at 3

and 48 h after ICH (6 rats at each time point) and in 6 sham-operated rats to determine the time window of PTPN22 expression after ICH. Another 72 rats were randomized equally into sham operation group

ICH group

ICH+negative control (ICH+NC) group

and ICH+PTPN22 interference group

and the neurological function score (mNSS) and brain water content were assessed at 24 h after ICH or the sham operation. Western blotting was used to detect the expression of cleaved interleukin-18 (cleaved IL-18)

cleaved-IL-1β and cleaved caspase-1 around the hematoma in the rats. Histomorphological changes of the brain tissues of the rats were observed using HE and Nissl staining

and the expression of myeloperoxidase (MPO) around the hematoma was detected using immunofluorescence staining.

Results

The expression of PTPN22 began to increase significantly at 12 h after ICH in the rats

peaked at 24 h and began to decrease at 48 h (

0.05). Compared with those in ICH+NC group

the rats in ICH+PTPN22 interference group had significantly lowered neurological scores and reduced brain water content (

0.05) with obviously alleviated brain tissue damage as shown by HE and Nissl staining. The expression of NLRP3

cleaved IL-1β

cleaved IL-18 and cleaved caspase-1 and the number of MPO-positive cells around the hematoma were all significantly lowered in PTPN22 interference group compared with ICH+NC gr

oup (

0.05).

Conclusion

Small interfering RNA-mediated interference of PTPN22 attenuates inflammatory response after ICH in rats by inhibiting the activation of NLRP3.

关键词

Keywords

references

KEEP R F, HUA Y, XI G H. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets[J]. Lancet Neurol, 2012, 11(8): 720-731. DOI: 10.1016/S1474-4422(12)70104-7.

VILLANI A C, LEMIRE M, FORTIN G, et al . Common variants in the NLRP3 region contribute to Crohn'sdisease susceptibility[J ] . Nat Genet, 2009, 41(1): 71-76. DOI: 10.1038/ng.285.

LIU C M, SHI B Z, ZHOU J S. Effects of thrombin on the secondary cerebral injury ofperihematomal tissues of rats after intracerebral hemorrhage[J]. Genet Mol Res, 2014, 13(2): 4617-4626. DOI: 10.4238/2014.June.18.4.

SPALINGER M R, LANG S, WEBER A, et al . Loss of protein tyrosine phosphatase nonreceptor type 22 regulates interferon-γ-induced signaling in human monocytes[J ] . Gastroenterology, 2013 , 144(5): 978-988.e10. DOI: 10.1053/j.gastro.2013.01.048.

SPALINGER M R, KASPER S, GOTTIER C, et al . NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN 22 [J ] . J Clin Invest, 2016, 126(11): 4388. DOI: 10.1172/JCI90897..

MOHAMED I N, ISHRAT T, FAGAN S C, et al . Role of inflammasome activation in the pathophysiology of vascular diseases of the neurovascular unit[J ] . Antioxid Redox Signal, 2015, 22(13): 1188-1206. DOI: 10.1089/ars.2014.6126.

LIU H X, ZHAO L, YUE L, et al . Pterostilbene attenuates early brain injury following subarachnoid hemorrhage via inhibition of the NLRP3 inflammasome and Nox2-related oxidative stress[J ] . Mol Neurobiol, 2017, 54(8): 5928-5940. DOI: 10.1007/s12035-016-0108-8.

REN H L, KONG Y, LIU Z J, et al . Selective NLRP3 (pyrin domain-containing protein 3) inflammasome inhibitor reduces brain injury after intracerebral hemorrhage[J ] . Stroke, 2018, 49(1): 184-192. DOI: 10.1161/STROKEAHA. 117.018904.

ELLIOTT E I, SUTTERWALA F S. Initiation and perpetuation of NLRP3inflammasome activation and assembly[J]. Immunol Rev, 2015, 265(1): 35-52. DOI: 10.1111/imr.12286.

HE Q, LI Z Y, WANG Y T, et al . Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction[J ] . Int Immunopharmacol, 2017, 50: 208-215. DOI: 10.1016/j.intimp.2017.06.029.

WANG Y T, MENG CC, ZHANG J Y, et al . Inhibition of GSK-3β alleviates cerebral ischemia/reperfusion injury in rats by suppressing NLRP3 inflammasome activation through autophagy[J ] . Int Immunopharmacol, 2019, 68: 234-241. DOI: 10.1016/j.intimp.2018.12.042.

YU C, HE Q, ZHENG J, et al . Sulforaphane improves outcomes and slows cerebral ischemic/reperfusion injury via inhibition of NLRP3 inflammasome activation in rats[J ] . Int Immunopharmacol, 2017, 45: 74-78. DOI: 10.1016/j.intimp.2017.01.034.

LI Z Y, HE Q, ZHAI X, et al . Foxo1-mediated inflammatory response after cerebral hemorrhage in rats[J ] . Neurosci Lett, 2016, 629: 131-136. DOI: 10.1016/j.neulet.2016.06.013.

WILKINSON D A, PANDEY A S, THOMPSON B G, et al . Inj ury mechanisms in acute intracerebral hemorrhage[J ] . Neuropharmacology, 2018, 134(Pt B): 240-248. DOI: 10.1016/j.neuropharm.2017.09.033.

WANG X, ARIMA H, YANG J, et al . Mannitol and outcome in intracerebral hemorrhage: propensity score and multivariable intensive blood pressure reduction in acute cerebral hemorrhage trial 2 results[J ] . Stroke, 2015, 46(10): 2762-2767. DOI: 10.1161/STROKEAHA.115.009357.

KURAMATSU J B, HUTTNER H B, SCHWAB S. Advances in the management ofintracerebral hemorrhage[J]. J Neural Transm (Vienna), 2013, 120(Suppl 1): S35-S41. DOI: 10.1007/s00702-013-1040-y.

SPALINGER M R, LANG S, VAVRICKA S R, et al . Protein tyrosine phosphatase non-receptor type 22 modulates NOD2-induced cytokine release and autophagy[J ] . PLoS ONE, 2013, 8(8): e72384. DOI: 10.1371/journal.pone.0072384.

SPALINGER M R, LANG S, GOTTIER C, et al . PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner[J ] . Autophagy, 2017, 13(9): 1590-1601. DOI: 10.1080/15548627.2017.1341453.

ZHANG J Y, ZAHIR N, JIANG Q H, et al . The autoimmune disease-a ssociated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness[J ] . Nat Genet, 2011, 43(9): 902-907. DOI: 10.1038/ng.904.

BAUER C, DUEWELL P, MAYER C, et al . Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome[J ] . Gut, 2010, 59(9): 1192-1199. DOI: 10.1136/gut.2009.197822.

ZAKI M H, BOYD K L, VOGEL P, et al . The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis[J ] . Immunity, 2010, 32(3): 379-391. DOI: 10.1016/j.immuni.2010.03.003.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Effects and underlying mechanisms of novel phenothiazine derivative DA414 in rats with intracerebral hemorrhage

Autophagy inducer spermidine improves brain injury after intracerebral hemorrhage

Notch1 regulates hippocampal neurogenesis and recovery of neurological function in mice after intracerebral hemorrhage

Myeloid-derived growth factor improves pyroptosis in H9c2 cells induced by high glucose

NDP-MSH activates melanocortin-3 receptor to attenuate oxidative stress and neuronal apoptosis in mice with intracerebral hemorrhage via PKC/ERK signaling pathway

Related Author

MA Yufan

WANG Bingqiao

LIN Sen

YANG Qingwu

QI Lingxiao

YAN Gaili

XUE Mengzhou

Jing CHEN

Related Institution

Department of Neurology， Second Affiliated Hospital， Army Medical University （Third Military Medical University）

Department of Cerebrovascular Diseases， Second Affiliated Hospital of Zhengzhou University, Zhengzhou University

Academy of Medical Sciences, Zhengzhou University

Department of Neurology, Baoji Gaoxin People's Hospital

Department of Neurology, Xinqiao Hospital, Third Military Medical University

⁰