4.7 Article

HSP60 plays a regulatory role in IL-1β-induced microglial inflammation via TLR4-p38 MAPK axis

期刊

JOURNAL OF NEUROINFLAMMATION
卷 13, 期 -, 页码 -

出版社

BIOMED CENTRAL LTD
DOI: 10.1186/s12974-016-0486-x

关键词

Microglia; IL-1 beta; HSP60; Inflammation; MAPK; p38; MEK3/6; TLR4

资金

  1. Department of Science and Technology, Government of India [SB/SO/HS-070/2013]
  2. Tata Innovation Fellowship, Department of Biotechnology, Government of India [BT/HRD/35/01/02/2014]
  3. DST Inspire faculty award from Department of Science and Technology, Government of India [IFA13-LSBM-90]
  4. Indian Council of Medical Research, Government of India [80/774/2012-ECD-I]
  5. Council of Scientific & Industrial Research, Government of India

向作者/读者索取更多资源

Background: IL-1 beta, also known as the master regulator of inflammation, is a potent pro-inflammatory cytokine secreted by activated microglia in response to pathogenic invasions or neurodegeneration. It initiates a vicious cycle of inflammation and orchestrates various molecular mechanisms involved in neuroinflammation. The role of IL-1 beta has been extensively studied in neurodegenerative disorders; however, molecular mechanisms underlying inflammation induced by IL-1 beta are still poorly understood. The objective of our study is the comprehensive identification of molecular circuitry involved in IL-1 beta-induced inflammation in microglia through protein profiling. Methods: To achieve our aim, we performed the proteomic analysis of N9 microglial cells with and without IL-1 beta treatment at different time points. Expression of HSP60 in response to IL-1 beta administration was checked by quantitative real-time PCR, immunoblotting, and immunofluorescence. Interaction of HSP60 with TLR4 was determined by co-immunoprecipitation. Inhibition of TLR4 was done using TLR4 inhibitor to reveal its effect on IL-1 beta-induced inflammation. Further, effect of HSP60 knockdown and overexpression were assessed on the inflammation in microglia. Specific MAPK inhibitors were used to reveal the downstream MAPK exclusively involved in HSP60-induced inflammation in microglia. Results: Total 21 proteins were found to be differentially expressed in response to IL-1 beta treatment in N9 microglial cells. In silico analysis of these proteins revealed unfolded protein response as one of the most significant molecular functions, and HSP60 turned out to be a key hub molecule. IL-1 beta induced the expression as well as secretion of HSP60 in extracellular milieu during inflammation of N9 cells. Secreted HSP60 binds to TLR4 and inhibition of TLR4 suppressed IL-1 beta-induced inflammation to a significant extent. Our knockdown and overexpression studies demonstrated that HSP60 increases the phosphorylation of ERK, JNK, and p38 MAPKs in N9 cells during inflammation. Specific inhibition of p38 by inhibitors suppressed HSP60-induced inflammation, thus pointed towards the major role of p38 MAPK rather than ERK1/2 and JNK in HSP60-induced inflammation. Furthermore, silencing of upstream modulator of p38, i. e., MEK3/6 also reduced HSP60-induced inflammation. Conclusions: IL-1 beta induces expression of HSP60 in N9 microglial cells that further augments inflammation via TLR4-p38 MAPK axis.

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