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  • Excessive inflammation is an early systemic

    2018-10-30

    Excessive inflammation is an early systemic inflammatory response that can result in multiple organ failure and even death (Leclerc et al., 2011). miRNAs enriched in exosomes play a pivotal role in regulating inflammation (Wang et al., 2015). miR-155 and miR-146a are two critical regulators of inflammation, as exosomal miR-146a administration represses inflammatory gene expression and reduces endotoxin-induced inflammation in mice (Alexander et al., 2015). miR-181c abrogates TLR4 expression by directly binding to its 3′-UTR to restrict the inflammatory response (Zhang et al., 2015). TLR4 is a key protein that has been reported to play an important role in inflammation (Ping et al., 2012). Since TLR4 was identified as the LPS receptor, it has been suggested to trigger all LPS responses, and macrophage is key causative participants in this process (Plociennikowska et al., 2015). Previous studies have shown that TLR4 expression in activated microglia mediates neuroinflammation through nuclear factor-κB (NF-κB) in response to STA-9090 injury (Mao et al., 2012). The NF-κB family consists of five members, including p105/p50, p100/p52, p65/Rel A, Rel B and c-Rel (Yu et al., 2009). In silent cells, NF-κB is kept inactive by binding to IκB proteins. Upon LPS stimulation, IκB proteins are targeted for degradation by the 26S proteasome after IκB kinase (IKK) phosphorylation (Yu et al., 2009). p65 can then translocate into the nucleus and initiate inflammatory gene expression. Hutchison ER et al. previously showed that miR-181 knockdown enhanced LPS-induced production of TNF-a, IL-6, IL-1β, IL-8 and HMGB1, while miR-181 overexpression resulted in a significant increase in anti-inflammatory cytokine IL-10 expression in the neuroinflammatory responses of astrocytes (Hutchison et al., 2013). In the serum of severe burn rats, hUCMSC-exosomes suppressed TNF-α and IL-1β secretion and increased IL-10 secretion. IL-10 is considered an anti-inflammatory cytokine, and a previous study found that macrophage-derived IL-10 is necessary for the effect of BMSCs in mouse sepsis models (Nemeth et al., 2009). In mouse macrophage cell line cultures, hUCMSC-exosomes downregulated TNF-α and IL-1β levels and upregulated IL-10 levels after LPS stimulation, suggesting an immunomodulatory effect in animal models similar to cultured cells. However, hUCMSC-exosomes do not affect the expression of TNF-α, IL-1β and IL-10 after 24h, suggesting that a second dose may be necessary in the burn rat models in future studies.
    Abbreviations
    The following is the supplementary data related to this article.
    Author Contributions
    Conflict of Interest Statements
    Acknowledgments The authors would like to thank Dr. Feng Xu for dynamic light scattering analysis and Dr. Sa Zhang for transmission electron microscopy analysis. The current study was supported by the National Science Foundation of China (grant nos. NSFC81372052, NSFC81571894, NSFC81501694, NSFC81471873), and the Nursery Fund of PLA General Hospital14KMM22.
    Introduction Cellular plasticity in mouse and human tissues can be modulated after fusion of bone marrow (BM)-derived cells with a variety of cells, such as neurons, hepatocytes, cardiomyocytes, and gut cells (Nygren et al., 2004; Doyonnas et al., 2004; Ogle et al., 2005; Johansson et al., 2008; de Jong et al., 2012). The hybrids produced can repair the function of these different cell types in a damaged organ (Wang et al., 2003; Johansson et al., 2008; Sanges et al., 2013). Parkinson\'s disease (PD) is one of the most common neurodegenerative disorders, and it affects about 1% of the population above the age of 60years (de Rijk et al., 1997). PD develops due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), with the consequent degeneration of tyrosine-hydroxylase fibers in the striatum (CPu, caudate-putamen), and dopamine (DA) depletion (de Rijk et al., 1997). No definitive cure is currently available for PD.