Stress, Inflammation and CVD

CVD was considered to be a leading cause of death worldwide. Large bodies of clinical trial pointed out that chronic stress, whether early life stress (Su et al., 2015) or adult stress has long been linked to increased coronary heart disease (CHD) risk. Childhood adversity especially severe physical and sexual abuse in childhood was found to strongly relate to higher morbidity of cardiovascular events in women (Rich-Edwards et al., 2012; Thurston et al., 2014). Children who are less expressive and cohesive in their original family exhibited more problematic cardiovascular risk factor profiles (Bleil et al., 2013). Those who experienced more family disruption events or early life family conflict had greater mean intima-media thickness (IMT), a subclinical marker of CVD risk (Bleil et al., 2013). In adulthood, work-related stressors such as low-income, high job demands combined with low control, shift work and workplace conflicts were mostly reported to be correlated to higher CVD risk (Bleil et al., 2013). Besides that, poor sleep quality under stress, discrimination emotion stress, such as anger, hostility and aggressiveness were also involved in coronary artery disease (Kop, 2003). On the contrast, effective stress management including positive emotions, optimism and life satisfaction were proved to have protective roles for CVD (Bleil et al., 2013).

While the biological mechanisms of stress increasing CVD risk are not well-known, chronic low-grade inflammatory load may emerge as a possible link as it is both elevated by chronic stress and contributed to early process, progression and thrombotic complications of atherosclerosis. IL-6 and CRP, the two important biomarkers of systematic inflammation, are considered indicative and potentially predictive for atherosclerosis (Tsirpanlis, 2005; Nadrowski et al., 2016). Coincidently, these two inflammatory indicators were elevated in different types of life stress. For instance, severe levels of childhood abuse were associated with a more elevated acute stress-induced IL-6 response, possibly due to reduced methylation of the IL-6 promoter (Janusek et al., 2017). Adults who had greater childhood adversity was reported to have more depressive symptoms and elevated concentrations of CRP (Janusek et al., 2017). Recent studies have suggested that CRP and IL-6 are mechanisms by which early adversity may contribute to CVD (Ridker et al., 2002; Albert et al., 2006; Graham et al., 2006). Work-related stressors have also been mentioned to correlate with elevated CRP and IL-6 (von Känel et al., 2008). In a recent study applied in black and white men, greater stressor-evoked reduction in high-frequency heart rate variability (HF-HRV) and were correlated with higher CRP and IL-6. In animal stress models (social isolation, social disruption, cold stress, severe chronic unpredictable stress), increased plaque size, elevated serum IL-6, NPY levels were observed. However, when single supplied with GC after Adrenalectomy, plaque size and serum inflammatory factors were decreased or did not change. This suggested that the possible mechanisms of stress-related inflammation in CVD may include SNS-mediated increases in NE and NPY. Noisy communities as life stressor induces significant increase in urine epinephrine and NE leading to hypertension (Seidman and Standring, 2010). NE promoted the production of inflammatory factors by facilitating the phosphorylation of MAPKs through activation of NE α receptor (Huang et al., 2012). NPY could elicit TGF-β1 and TNFα production in macrophage-like cell line RAW264.7 via Y1 receptor (von Känel et al., 2008). NPY could also directly activate the HMGB1 release and cytoplasmic translocation from the macrophage (Zhou et al., 2013). Inflammation has also been shown to correlate with endothelial dysfunction and relate to the renin-angiotensin system (Li et al., 2012).

Overall, the possible mechanism could be summarized as follows. Stress may activate through SNS system to release NE and NPY, these two stress hormones further facilitate the phosphorylation of MAPKs or HMGB1 release, therefore inducing systematic inflammation (IL-6, CRP) to promote or accelerate CVD development. Anti-inflammatory drugs may have synergistic effect with conventional antihypertensive drugs on the prevention and treatment of stress-related CVD.

Stress, Inflammation and Metabolic Disease

Stressful events could motivate unhealthy food choices (Kuo et al., 2008). These unhealthy foods are frequently associated with morbid obesity, type 2 diabetes mellitus, metabolic syndrome and NAFLD (Mikolajczyk et al., 2009). Stress enhances both post-meal peaks of triglycerides and delays lipids clearance (Kiecolt-Glaser, 2010). As shown in Hoorn’s study, stressful life events, which indicate chronic psychological stress, are associated with higher prevalence of undetected type 2 diabetes (Mooy et al., 2000). A recent prospective study supported this view, and provided further evidence (Cosgrove et al., 2012). Furthermore, effective stress management training or mindfulness-based stress reduction training has been proved to have clinically significant benefits on patients with type 2 diabetes. On the contrary, highly anxious patients did not obtain more improvement from the training (Rosenzweig et al., 2007).

Insulin resistance frequently develops during acute or chronic stress (Tsuneki et al., 2013). Insufficient insulin secretion to compensate for insulin resistance is also the characteristic of Type 2 diabetes. Insulin resistance, visceral obesity, dyslipidemia, type 2 diabetes mellitus and metabolic syndrome are key risk factors in the development and progression of NAFLD. At the intersection of metabolism and immunity, inflammation may be an important link between stress and metabolic disease. Intense stress over-activates the immune system, leading to the imbalance between inflammation and anti-inflammation. The activated stress pathways can initiate or exacerbate inflammation and culminate in hepatocyte cell death and liver damage by apoptosis (Gentile et al., 2011). IL-1 family members might be involved in controlling insulin resistance and metabolic inflammation in various obesity-associated disorders (Kamari et al., 2011; Tilg and Moschen, 2011; Tack et al., 2012). It is reported that the modulator of IL-1, NLRP6 and NLRP3 inflammasomes negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome (Zhu et al., 2006). Inflammatory transcriptor NF-κB and JNK activator protein-1 (AP-1) emerged as a central metabolic regulator (Wellen and Hotamisligil, 2005). Enhanced hepatic NF-κB activity was observed in high fat fed-mice (Day, 2006). NAFLD is regularly associated with lipometabolic disorders and inflammatory reactions, especially in the nonalcoholic steatohepatitis (NASH) stage (Liu et al., 2012). Chronic, low-grade inflammatory process is also the characteristic of diabetes. The “two-hit” hypothesis for the pathogenesis of NAFLD implicates inflammation as the link between steatosis and steatohepatitis. Inflammatory stress may aggravate the progression of NAFLD by increasing cholesterol influx and reducing cholesterol efflux especially during the second-hit stage of NAFLD (Ma et al., 2008).

Metabolism-controlling stress hormones, especially GCs and NE could exert anti-insulin effects, and in the long run induce insulin resistance. GC receptor antagonist RU486 and adrenalectomy reduce the occurrence of insulin resistance. High concentration of NE in plasma could raise fasting glucose and reduce glucose tolerance, possibly mediated by lipolysis and increased fatty acid concentrations (Marangou et al., 1988). Adrenergic receptor activation may directly affect the insulin signaling pathway or cellular glucose transport (Mulder et al., 2005). Additionally, GCs and NE could also regulate inflammation. In diabetes, elevated circulating levels of proinflammatory cytokines are originally thought to be the adipocytes themselves in response to obesity. However, an increasing number of evidence suggests that obesity results in increased number of macrophages and changes in the activation status of these cells. Therefore, adipose tissue macrophages produce a significant proportion of the inflammatory factors that are upregulated by obesity (Donath and Shoelson, 2011). Inflammatory cytokines produced by various cells such as Kupffer cells, macrophages, neutrophils, monocytes, adipocytes and hepatocytes, have critical roles in lipid metabolism and hepatic inflammation that promote liver damage. Antagonizing or inhibiting TNFα, significantly improved NAFLD and is currently tested in human NASH (chronic hepatic inflammation; Gastaldelli et al., 2009; Musso et al., 2009). Furthermore, TNFR1 ectodomain shedding could attenuate the progression from “simple steatosis” towards NASH (Aparicio-Vergara et al., 2013).

Stress, Inflammation and Depression

Stressful experiences are fundamental in the provocation of major depression of disorder (MDD). HPA axis activation and hypercortisolemia often seen in depressed patients may represent increased stress hormones, CRH and ACTH secretion (Capuron et al., 2003). MAPK pathways have been proved to increase the activity of serotonin membrane transporters, the most important neurotransmitter associated with depression (Zhu et al., 2006).

Recently, the “cytokine hypothesis” or “macrophage theory” has been suggested in MDD. The main idea of inflammatory depression is the activation of the inflammatory immune response, particularly the synthesis of cytokines, which might influence neurochemicals and contribute to MDD (Smith, 1991). Stress can facilitate the development of depressive-like behavior by promoting inflammatory cytokine expression (Norman et al., 2010). Additionally, a new pathway—kynurenine pathway (KP) has attracted much more attention in cytokine hypothesis. Proinflammatory cytokines activate KP to affect tryptophan metabolism and produce neurotoxin, which either reduces serotonin synthesis or fastens the reuptake of serotonin (Miura et al., 2008).

Data from animal models and clinical patients prove the role of inflammation in depression. Exposure to inflammatory cytokines such as TNFα, IFNα and IL-1β or cytokine inducers such as LPS or vaccination has been shown to lead to marked behavioral alterations in human and rodent. Elevated inflammatory mediators such as cytokines and their soluble receptors, chemokines, acute phase proteins, adhesion molecules and prostaglandins (PGs) have also been found with depression in peripheral blood, CNS and cerebrospinal fluid (CSF; Miller et al., 2009; Dowlati et al., 2010; Norman et al., 2010; Raison et al., 2010). We use chronic stress to establish depression model. Four-week chronic stress exposure significantly upregulates the inflammatory cytokines such as TNFα, IL-18, IL-1β and inflammatory inducible NOS (iNOS) expression (Peng et al., 2012). Accompanying the upregulation of proinflammatory cytokines, depressive-like behaviors were established. In contrast, blocking iNOS or inflammatory cytokines with 1400W (Peng et al., 2012) or minocycline could abrogate the depressive-like behavior induced by stress (Peng et al., 2012). In fact, some clinical antidepressants really have the role of anti-inflammation. Antidepressant drug and nonsteroidal anti-inflammatory drugs (NSAIDs) like minocycline, decrease blood levels of IL-6, attenuate microglial activation and central cytokine secretion and behavioral changes (Henry et al., 2008).

Inflammasomes are multi-molecular platforms, driving the maturation and secretion of pro-inflammatory factors IL-1β and IL-18 to take part in innate immune defenses (Schroder and Tschopp, 2010). We found that NLRP3 inflammasome is involved in LPS-induced mice depressive-like behaviors (Zhang et al., 2014). Recent research showed protective effect of caspase-1 inhibition on brain function, and gut microbiota induced depressive- and anxiety-like behaviors (Wong et al., 2016).

Stress, Inflammation and Neurodegenerative Diseases

The role of stress and inflammation are being recognized in neurodegenerative disease. AD and PD are the two most common neurodegenerative diseases. Extracellular amyloid β protein (Aβ) accumulation is currently seen as a key step in the pathogenesis of AD. PD is characterized by progressive loss of nigrostriatal dopaminergic (DA) neurons and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. The potential etiology and molecular mechanisms underlying the pathogenesis of AD and PD remains unknown and have not been completely elucidated. However, some progress has been made in identifying the risk factors. During the last two to three decades, increasing evidence from animal and clinical studies has implicated stress and neuroinflammation as risk factors and may play a fundamental part in the pathogenesis of AD and PD.

Epidemiological, clinical studies and animal model of AD suggest that stress and inflammation interact with processing and deposit of Aβ, contributing to the pathogenesis of AD (Kunjathoor et al., 2004). Hypercortisolemia is one of the features found in patients diagnosed of AD. An array of elevated inflammatory mediators including TNFα, IL-1, PGE₂, NF-κB, COX-2 and MCP-1 has been detected from patients with AD (Wyss-Coray, 2006; Comi et al., 2010) and correlated with the amount of Aβ and the severity of AD pathogenesis (Hoshino et al., 2009; Chen et al., 2012). Researchers also observed increased cytokines such as TNFα, IL-1β and IFN in the substantianigra of PD patients (Nagatsu and Sawada, 2005). Activation of the systemic innate immune system by infection may participate in the early stages of AD pathogenesis (Perry et al., 2007). Neuroinflammation induces degenerative changes in the DA system, which lowers the set point toward neuronal dysfunction and degeneration (Morand and Leech, 1999). Proinflammatory lipid mediators include PGs and platelet activating factor, together with cytokines may significantly affect the progressive neurodegeneration in PD (Busillo et al., 2011). Mice with microglial activation-induced oxidative stress and inflammation, and nigrostriatal DA neuronal damage have been used to serve as an experimental model of PD. Stress exposure increased neuroinflammation in AD and is characterized by astrogliosis, increased inflammatory gene expression and lipid peroxidation (Perez Nievas et al., 2011). It has been confirmed with the changes in glial cells surrounding the senile plaques. Genetic research demonstrates that inherited variations in inflammatory response mechanisms may influence AD pathogenesis (Grimaldi et al., 2000; Nicoll et al., 2000). In contrast, anti-inflammatory agents such as NSAIDs and antioxidant therapy might protect against the development of AD. Long-term use of NSAIDs, inhibitors of COX, suppression of neuroinflammation by glial inhibitors, delays the initiation and reduces the risk of AD (Tsukuda et al., 2009; Chen et al., 2012). In consistent with epidemiology, nicotine was proved to have a neuroprotective effect on DA neurons by means of an anti-inflammatory mechanism mediated by the regulation of microglial activation (Park et al., 2007). Therefore, new potent neuroprotective therapies for PD might be taken into account by focusing on critical inflammatory mechanisms, such as cytokine-induced neurotoxicity (Morand and Leech, 1999). A variety of preclinical studies have corroborated the therapeutic potential of targeting cholinergic anti-inflammatory pathway (Bencherif et al., 2011).

Limitations

Stress-induced inflammation described here may be relevant to understand the common mechanisms of stress-related diseases. However, quite a few unanswered questions still need to be further discussed. For instance, besides inflammation, is there the crosstalk among inflammation and other related pathways such as cell stress? Is there the specific cell or pathway for the specific stress-related disease? Can anti-inflammatory specifically affect neuroinflammation without modulating periphery immunity for CNS disease? More crucially, to reach clinical application, anti-inflammatory therapies will need to accurately target on specific cells and pathways in CNS, which are fundamentally important in human disease pathogenesis. All these limitations could be the next research key point. Breaking through these barriers would make great progress on the treatment of stress-related diseases.

The authors acknowledge the funding support provided by National Natural Science Foundation of China 81571169, 31371200, Military Medical Research Foundation AHJ16J001, National Instrumentation Program 2013YQ19046708, and the Natural Science Foundation of Shanghai (17ZR1437800).