The proinflammatory cytokines and chemokines

The proinflammatory cytokines and chemokines, including IL-1β, TNF-α and MCP-1, mediate acute and chronic inflammation and play a role in the development of hypertension [2, [51], [52], [53]], cardiovascular diseases [4, 54] and renal injury [55, 56] in animal models and humans. Concerning the possible link between leukocyte RAS components and these proinflammatory cytokines, MCP-1 and IL-1β were significantly upregulated in the kidney in angiotensin II-infused chimeric mice that lacked AT1R in the bone marrow compared with control animals [12]. In addition, macrophage-specific AT1R deficiency exacerbated UUO-induced renal fibrosis through the activation of the IL-1 receptor pathway [15]. The results of the present study, which used bone marrow-transplanted mice, showed that leukocyte IL-1β expression was significantly upregulated in bone marrow ATRAP-deficient mice, suggesting that leukocyte ATRAP level increases to mitigate inflammation. The present study has several limitations. First, we are not able to clearly state the advantage of the measurement of leukocyte ATRAP mRNA in comparison to the measurement of established inflammatory markers, such as hsCRP, in the clinical setting. To clarify this issue, we will examine the clinical significance of the absolute leukocyte ATRAP mRNA level, as measured by ddPCR, with regard to the mortality and/or cardiovascular outcome in a future longitudinal study. Second, it is not clear whether human serum, as a blocking solution for Fc receptor, affects leukocyte gene expression in experiments in which leukocytes are sorted using flow cytometry.
Conflicts of interest
Financial support This research was supported by The Jikei University Graduate Research Fund. This work was also supported by grants from the Yokohama Foundation for advancement of Medical Science, by a Uehara Memorial Foundation grant, Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, grants from SENSHIN Medical Research, the Banyu Life Science Foundation International, the Salt Science Research Foundation (1733), the Kanae Foundation for the Promotion of Medical Science and a grant-in-aid from The Cardiovascular Research Fund, Tokyo, Japan.
Author contributions
Introduction Mounting evidence indicates that inflammation and oxidative damage has a critical role in the pathogenesis of the selinexor diseases such as Alzheimer's disease, Parkinson's disease, depression and many of other pathological conditions in the central nervous system (CNS) [1,2]. Blocking or minimizing the neuroinflammation has been suggested as a strategy for delaying the onset neurodegenerative diseases [3]. In the rodent model of peripheral inflammation Escherichia coli lipopolysaccharide (LPS) systemically administrated and LPS, by binding to CD14 (cluster of differentiation 14) receptors and activating toll-like receptor 4 (TLR4) induces the secretion of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and other pro-inflammatory mediators [4]. Systemic inflammation signals to the brain via humoral, cellular, and neural routes. LPS can signal through the circumventricular organs, which lack a blood-brain barrier (BBB), binds to receptors on the endothelial cells and stimulate them to secrete cytokines directly into the brain parenchyma. LPS also induces active transport of cytokines through the BBB and direct activation of vagal afferents by circulating cytokines [[4], [5], [6]]. Brain uptake of LPS has been reported to be limited [7] however, it has been reported that systemic injection of LPS is followed by an increased level of expression of TLR4 on microglia that may reflect importance of direct actions of peripheral LPS in the brain inflammation [8]. A set of recent studies have reported that renin-angiotensin system (RAS) has a critical role in the brain inflammation [9]. Angiotensin II (Ang II) is the main active factor of the RAS, which has physiological and pathophysiological functions not only as a peripheral hormone but also as a local modulator [10]. Besides of a well-known systemic RAS, a local one has been reported to be present in the brain [[11], [12], [13]]. Ang II is involved in several functions including, but not limited to the sympathetic and neuroendocrine outputs, stress response, regulation of cerebral blood flow and the most recently discovered, the regulation of brain inflammation [14,15]. The most of the effects of Ang II are mediated by stimulating of Ang II type I receptor (AT1R) and over-activation of AT1R in the brain is associated with neuroinflammation, microglial activation, oxidative stress and neuronal loss [[14], [15], [16], [17]]. It has been reported that intracerebroventricular administration of Ang II in rats leads to activation of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, increasing of expression of the M1 microglial phenotype maker, inducible nitric oxide synthase (iNOS) and reduction of expression of M2 microglial phenotype marker, arginase 1 (Arg-1) [14]. There is also evidence that AT1R blockers (ARBs) are effective compounds in the controlling of neuroinflammation and they are potentially opening a new therapeutic path for brain disorders. Previous studies showed that inhibition of angiotensin converting enzyme (ACE) or blocking of AT1R by ARBs ameliorates microglial activation, cytokine production, oxidative stress, apoptosis and neuronal loss and the behavioral consequences of inflammation [[17], [18], [19], [20], [21], [22], [23], [24]]. However, ARBs have been reported to be more effective in the controlling of brain inflammation than the ACE inhibitors [25]. The aim of this study was to examine the effects of Ang II receptor blocker, losartan on the brain inflammation, oxidative stress and behavioral consequences of systemic LPS injection.