Inflammatory mediators ATP and S100A12 activate the NLRP3 inflammasome to induce MUC5AC production in airway epithelial cells
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Authors: Kim, Karam; Kim, Hye Jeong; Binas, Bert; Kang, Jin Hyun; Chung, Il Yup
Danger-associated molecular patterns (DAMPS) play a proinflammatory role in the pathogenesis of airway obstructive diseases such as severe asthma and chronic obstructive pulmonary disease. The NLRP3 inflammasome is a cytosolic multiprotein platform that activates the caspase-1 pathway in response to inflammatory stimuli such as DAMPs. ATP and S100 proteins are newly identified DAMPs that accumulate in inflamed airways. We previously demonstrated that S100A8, S100A9, and S100A12 induce production and secretion of MUC5AC, a major mucin in the conducting airway mucosa. The purpose of this study was to determine the involvement of NLRP3 inflammasome in, and the contribution of ATP to, 5100 protein-induced MUC5AC production by NCI-H292 mucoepidermoid carcinoma cells. Stimulation with either S100A12 or ATP led to MUC5AC production at comparable levels. Simultaneous treatment with both stimuli resulted in additive increases in NLRP3, active caspase-1, IL-1 beta, NLRP3/caspase-1 colocalization, and MUC5AC. NLRP3 siRNA or inhibitors of NF-kappa B, NLRP3 inflammasome oligomerization, or caspase-1 nearly completely inhibited ATP- and S100A12-mediated MUC5AC production. Furthermore, S100A12-as well as ATP-mediated MUC5AC production was almost equally blunted by both nonspecific and specific antagonists of the purinergic receptor P2X7, a principal receptor mediating NLRP3 inflammasome activation by ATP. Thus, these two danger signals contribute to MUC5AC production in airway epithelial cells through overlapping signaling pathways for NLRP3 inflammasome activation. (C) 2018 Elsevier Inc. All rights reserved.
S100A8/A9 induces microglia activation and promotes the apoptosis of oligodendrocyte precursor cells by activating the NF-kappa B signaling pathway
BRAIN RESEARCH BULLETIN
Authors: Wu, Meili; Xu, Lu; Wang, Yu; Zhou, Ning; Zhen, Fei; Zhang, Ying; Qu, Xuebin; Fan, Hongbin; Liu, Sihan; Chen, Yan; Yao, Ruiqin
S100A8/A9, a heterodimer complex composed of calcium-binding proteins S100A8 and S100A9, is significantly increased in the serum of multiple sclerosis (MS) patients. Relevant reports have revealed that MS pathology is commonly associated with the activation of microglial cells and the damage of oligodendrocyte precursor cells (OPCs). Moreover, microglia activation following stimulation increases the expression of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), which further exacerbate the damage to OPCs. In this study, we were the first to confirm that S100A8/A9 treatment induced the activation, proliferation and migration of the murine microglia cell line BV-2; moreover, this treatment caused the cells to switch from an anti-inflammatory activated (M2) phenotype to a pro-inflammatory activated (M1) phenotype. Meanwhile, the level of the phosphorylated nuclear factor-kappa B (p-NF-kappa B) P65 protein was remarkably elevated, and the production of pro-inflammatory factors (IL-1 beta, TNF-alpha, MMP-9) and chemokines (CCL2, CCL3, CXCL10) was also increased in the S100A8/A9-treated BV-2 microglial cells. Inhibition of NF-kappa B P65 phosphorylation reversed the effects of S100A8/A9 on the production of pro-inflammatory factors and chemokines. We also explored the effects of S100A8/A9 and S100A8/A9-activated BV-2 microglial cells on the viability of OPCs. The results showed that both the S100A8/A9 complex and the conditioned medium (CM) of the S100A8/A9-activated BV-2 microglial cells resulted in OPC apoptosis, which was more pronounced in the case of the CM treatment. However, OPC apoptosis in the CM group was obviously decreased through the inhibition of NF-kappa B p65 phosphorylation. This study indicates that S100A8/A9 induces the activation of BV-2 microglial cells and promotes the production of pro-inflammatory factors by activating the NF-kappa B signaling pathway, which further exacerbates OPC damage.