Low glucocorticoids in stress-related disorders: the role of inflammation

Abstract

There is evidence that plasma cortisol concentration can be either increased or decreased in patients with depression and related anxiety and stress-related disorders; the exact pathophysiological mechanisms of this state are not almost clear. Several distinct theories were proposed and mechanisms, which could lead to decreased glucocorticoid signaling and/or levels, were described. However, there is a possible drawback in almost all the theories proposed: insufficient attention to the inflammatory process, which is undoubtedly present in several stress-related disorders, including post-traumatic stress disorder (PTSD). Previous studies only briefly mentioned the presence of an inflammatory reaction’s signs in PTSD, without giving it due importance, although recognizing that it can affect the course of the disease. With that, the state of biochemical changes, characterized by the low glucocorticoids, glucocorticoid receptor’s resistance and the signs of the persistent inflammation (with the high levels of circulating cytokines) might be observed not only in PTSD but in coronary heart diseases and systemic chronic inflammatory diseases (rheumatoid arthritis) as well. That is why the present review aims to depict the pathophysiological mechanisms, which lead to a decrease in glucocorticoids in PTSD due to the action of inflammatory stimuli. We described changes in the glucocorticoid system and inflammatory reaction as parts of an integral system, where glucocorticoids and the glucocorticoid receptor reside at the apex of a regulatory network that blocks several inflammatory pathways, while decreased glucocorticoid signaling and/or level leads to unchecked inflammatory reactions to promote pathologies such as PTSD.

LAY SUMMARY

• This review emphasizes the importance of inflammatory reaction in the development of puzzling conditions sometimes observed in severe diseases including post-traumatic stress disorder — the decreased levels of glucocorticoids in the blood. Following the classical concepts, one would expect an increase in glucocorticoid hormones, since they are part of the feedback mechanism in the immune system, which reduces stress and inflammation. However, low levels of glucocorticoid hormones are also observed. Thus, this review describes potential mechanisms, which can lead to the development of such a state.

Keywords:

• Cytokines
• hypocortisolemia
• inflammation
• monoamine oxidase
• post-traumatic stress disorder
• PTSD

Introduction

The earliest evidence that chronic stress was associated with reduced daily output of glucocorticoids (Bourne et al., 1967; Friedman et al., 1963) puzzled the stress research community since it contradicted a well-accepted paradigm that stress increases glucocorticoid secretion. Later studies, however, confirmed that chronic stress may be indeed associated with decreased glucocorticoid signaling (McEwen, 2000; Tseilikman et al., 2020). Blunted glucocorticoid signaling was also observed in patients with several stress-related disorders, such as post-traumatic stress disorder (PTSD; Smith et al., 1989; Ströhle et al., 2008; Zaba et al., 2015), depression (Lopes et al., 2012), high trait anxiety (Duncko et al., 2006; Jezova et al., 2004), and panic disorder (Jezova et al., 2010; Petrowski et al., 2010). Decreased circulating baseline glucocorticoid levels were observed in animal models of PTSD (Boero et al., 2018; Dremencov et al., 2019; Lazuko et al., 2018; Whitaker et al., 2016).

Several distinct theories were proposed and mechanisms, which could lead to the blunted glucocorticoid signaling were described. Among others, the development model whereby hypocortisolism develops via the hypoactivity of the HPA axis after prolonged periods of chronic stress have been proposed (Hellhammer & Wade, 1993). Thus, the frailty (Morrison et al., 2001; Oldehinkel et al., 2001) or overstimulation of the HPA axis (Fries et al., 2005; Perrin et al., 2019) were shown to drive the exhaustion of the HPA axis, which may lead to hypocortisolemia. An increase in the hypothalamic release of corticotropin-releasing factor (CRF), leading to subsequent adaptive downregulation of CFR receptors at the level of pituitary gland also has been proposed (Hauger et al., 1990). According to Yehuda, (2001), impaired glucocorticoid signaling results from enhanced negative feedback by glucocorticoids, which is secondary to an increased sensitivity of glucocorticoid receptors (GR) in target tissues, while the duration, intensity, number and chronicity of stressors may further pronounce these effects (Fries et al., 2005; Miller et al., 2007). Later on, several mechanisms of the inadequate GR and monoamines signaling, metabolism and distribution typical for PTSD were described (Bierer et al., 2014; Geuze et al., 2012; Grinchii et al., 2018; Pivac et al., 2007), with the hypothesis, based on the presumption of the increased activity of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and CYP3A and decreased of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) leading to higher levels of 11-dehydrocorticosterone and lower levels of basal glucocorticoids being among them (Tseilikman et al., 2020). The peculiarities in neural interactions between prefrontal, amygdala, and hippocampal structures in PTSD were also studied (Morey et al., 2016; Woon & Hedges, 2008). Finally, the results of meta-analysis supported the evidence of prenatal programing of the axis, primarily on baseline cortisol measures and, disconcertingly, equivalent effect sizes for hyper and hypo-secretion (Pearson et al., 2015). Mounting evidence was emerging for prenatal development as a time during which programing of the axis might occur; however, whether those means elevations or suppressions were not completely clear (Koss & Gunnar, 2018).

However, there is a possible drawback in almost all the theories proposed: insufficient attention to the inflammatory process, which is undoubtedly present in PTSD. Previous studies only briefly mentioned the presence of an inflammatory reaction’s signs in PTSD, without giving it due to importance, although recognizing that it can affect the course of the disease or compound variabilities between various studies (Hori & Kim, 2019; Perrin et al., 2019; Tseilikman et al., 2020).

With that, numerous studies involving human subjects and animal experiments have revealed a possible linkage between inflammatory conditions and PTSD, as their results indicated, the signs of the inflammatory reaction manifested itself in increased levels of pro-inflammatory cytokines, such as Il-1, IL-6, TNF-a (reviewed in Gill et al., 2009; Wang & Young, 2016), elevations in RBC, WBC, platelets (Lindqvist et al., 2017), levels of CRP (Michopoulos et al., 2015) and pre-activating of PBMCs (Gola et al., 2013). Moreover, the higher pro-inflammatory scores in subjects with PTSD were revealed even after controlling for other factors (Lindqvist et al., 2014). While levels of anti-inflammatory cytokines have been less frequently measured in subjects with PTSD, there have been some studies indicating reduced levels of these anti-inflammatory mediators, including IL-4, IL-10 and TGF-β, number of lymphocytes, number of T cells, NK cell activity, and total amounts of IFN-gamma (Von et al., 2007; Teche et al., 2017). The imbalances in immune cell compositions in subjects with PTSD revealed itself in the increase in numbers of pro-inflammatory cells and the reduction of anti-inflammatory cells (Sommershof et al., 2009; Zhou et al., 2014).

That is why the present review aims to depict the pathophysiological mechanisms, which lead to the development of hypocortisolemia in PTSD due to the action of inflammatory stimuli.

11β-HSD activity

Cortisone is inactive and requires metabolism to cortisol catalyzed by 11β-HSD1. The liver is the major organ for converting cortisone to cortisol, but this also occurs in multiple other tissues including the brain. Conversion of cortisol to cortisone is mainly by the kidney, via 11β-HSD2.

With that, corticosteroid metabolism significantly changes in inflammatory conditions (Ichikawa et al., 1977), which suggests an increase in 11β-HSD1 activity, which increases cortisone metabolic clearance and the cortisol/cortisone ratio (Edwards, 2012). Hardy et al. (2006) investigating local corticosteroid metabolism in fibroblasts from rheumatoid arthritis and osteoarthritis patients revealed that 11β-HSD1 expression has increased after TNF-α or IL-1β with an associated increase in enzyme activity (Hardy et al., 2006). Stress was also shown to increase the adrenal and hepatic (Quinkler et al., 2003) activities and macrophage expression of 11β-HSD1 (Sesti-Costa et al., 2012). Later on, chemical inhibitor studies confirmed that the increase in 11β-HSD1 expression with TNFα)/IL-1β occurred via the proximal HSD11B1 gene promoter and depended on NF-κB signaling (Ahasan et al., 2012). The situation might be different in other cell types such as peripheral blood mononuclear cells (Straub & Cutolo, 2016), but altogether this suggests that local glucocorticoid production is part of the normal response to inflammation (Edwards, 2012).

Inflammation causes the changes in 11β-HSD2 activity as well, and the changes in its activity were revealed not only in inflammatory diseases (Hardy et al., 2006), but also in stress and PTSD (Igarreta et al., 1999; Zallocchi et al., 2004; Bierer et al., 2014). There is evidence of both an increase (Bierer et al., 2014; Straub & Cutolo, 2016) and a decrease (Stegk et al., 2009; Tsugita et al., 2008) in 11β-HSD2 activity, depending on the tissues/organs where the activity was determined. Thus, the increase in 11β-HSD2 activity was detected in immune cells (Olsen et al., 2004) and mixed synovial cells (Schmidt et al., 2005), in kidneys (Igarreta et al., 1999) and brain (Alderman & Vijayan, 2012) of stressed animals and adrenal glands of animals with PTSD (Tselikman, 2019), which could result in lower cortisol levels at the inflammatory site.

The consequences of changes in 11β-HSD1/11β-HSD2 activity in PTSD due to the action of pro-inflammatory cytokines cannot be overestimated. 11β-HSD-1 amplifies glucocorticoid feedback on the HPA axis and is an important regulator of neuronal glucocorticoid exposure under both basal and stress conditions in vivo (Harris et al., 2001). Thus, 11β-HSD1-deficient mice showed elevated plasma corticosterone and ACTH levels, suggesting abnormal HPA control and exaggerated ACTH and corticosterone responses to restraint stress, suggesting diminished glucocorticoid feedback, while the 11β-HSD1 excess might have the reverse effect (lower cortisol, diminished response to stress, reduced 24-h glucocorticoid secretion, and relative adrenal atrophy) (Harris et al., 2001). Moreover, liver glucocorticoid metabolism (intensified in PTSD) may influence both basal and stress-associated HPA functions without any alteration in hypothalamic 11β-HSD1 activity (Paterson et al., 2007). Regeneration of glucocorticoids by 11β-HSD1 in the liver normalizes all aspects of HPA axis dysregulation in 11β-HSD1-deficient mice, without restoration of enzyme activity in key feedback areas of the forebrain, and therefore, hepatic glucocorticoid metabolism influences basal as well as stress-associated functions of the HPA axis (Paterson et al., 2007).

It should be noted, that not only cytokines but also the stress-induced change in the level of neurotransmitters could also modulate the activity of 11β-HSD. It has been demonstrated that an increase in the messenger cAMP of the β‐adrenergic signaling pathway inhibits both 11β‐HSD1 and 11β‐HSD2 (Hammami & Siiteri, 1991), while adenosine was shown to increase cortisone reactivation (Ferguson et al., 1999) and to inhibit (as isoproterenol, a β‐adrenergic receptor agonist) cortisol inactivation (Schmidt et al., 2005), while stress-mediated catecholamines induce rapid, reversible decreases in 11β-HSD2 mRNA expression (Sarkar et al., 2001). These results indicated that sympathetic neurotransmitters increase cortisol by inhibiting its inactivation or by increasing the reactivation of cortisone and by this, shift the balance of corticosteroids (Schmidt et al., 2005). Moreover, stress reaction, by enhancing intracellular active glucocorticoids, contributes to producing increased PEPCK activity, with the consequent rise in glycemia (Altuna et al., 2006), which in turn leads to the development of a whole cascade of pathological reactions.

In general, with PTSD, the following sequence of changes may well occur (Figure 1): the prolonged action of pro-inflammatory cytokines causes an increase in hepatic 11β-HSD-1 activity and tissue-depended changes in 11β-HSD-2 activity, with the hepatic production of cortisol higher than adrenal production and augmentation of active glucocorticoid levels, which lead to HPA axis dysregulation and decrease in adrenocorticotropic hormone (ACTH), and, due to the feedback mechanism to the appearance of hypocortisolemia. Thereby, cortisol production becomes more independent of central brain-derived hormonal regulation.

Figure 1. Pathophysiology of the decreased glucocorticoids in inflammatory state. Glucocorticoid level changes are shown in the example of cortisol. The prolonged action of pro-inflammatory cytokines (A) causes an increase in hepatic 11β-HSD-1 activity (1) and tissue-depended changes in 11β-HSD-2 activity (2), with the hepatic production of cortisol higher than adrenal production and augmentation of active glucocorticoid levels, which lead to HPA axis dysregulation and decrease in adrenocorticotropic hormone (ACTH), and, due to the feedback mechanism to the decreased levels of glucocorticoids (state F). Thereby, cortisol production (B) becomes more independent of central brain-derived hormonal regulation. Pro-inflammatory cytokines also cause the decrease in MAO-A activity (3) and lead to blunted glucocorticoid signaling in tissues (C) and, aside from the direct action on adrenal gland morphology and function (3), also causes the glucocorticoid substrate deficiency (4), lowing the HDL levels. Altogether, these lead to the pathological picture with decreased glucocorticoids and the signs of system inflammatory reaction, typical for several diseases (F).

Glucocorticoid signaling, GR receptors

Glucocorticoid signaling is mediated by the high-affinity mineralocorticoid receptor (MR) expressed predominantly in the limbic structures and the widely distributed low-affinity GR. MR in the limbic structures, particularly the hippocampus, is in charge of the maintenance of a basal state of stress system activity and is involved in the initial phase of the stress response (Douglas Bremner 2019). The GR facilitates the termination of the stress response by negative feedback, and thus is central to the regulation of glucocorticoids levels (Douglas Bremner 2019)

The changes in GR density, binding activity, and sensitivity, as well as changes in the GR isoform ratio, were described in inflammatory conditions, stress, and PTSD. The first studies in patients with PTSD revealed the higher density of GR in leukocytes, which correlated with the severity of PTSD symptoms (Yehuda et al., 1991; Yehuda et al., 1993). Later on, similar results were obtained in combat exposed veterans with PTSD which revealed the higher GR density in both combat-related PTSD patients and combat exposed controls compared to healthy controls (Yehuda et al., 1995). Subjects with diagnosed PTSD after being sexually abused also had a higher mean leukocyte GR density (Stein et al., 1997). However, other studies reported no difference in baseline and post DST leukocyte GR density between PTSD patients and controls (Yehuda et al., 2002). Moreover, in several studies, GR density was reported to be significantly lower in patients with PTSD and compared to healthy controls (Gotovac et al., 2003; de Kloet et al., 2007). The effect of inflammatory reaction which accompanies PTSD on GR density is also not clear: the reduced GRα expression was shown to be correlated to the upregulation of the inflammatory genes in monocytes (Carvalho et al., 2014), while similar GR numbers to controls were shown in patients with the systemic low-grade inflammatory state (Ysrraelit et al., 2008) and even animals with SIRS (Hoffman et al., 2015).

The data of GR binding activity and sensitivity also varies. Enhanced glucocorticoid sensitivity in peripheral mononuclear blood cells was described (Rohleder et al., 2004; Yehuda et al., 2004), although T cells in veterans with PTSD revealed the decreased glucocorticoid sensitivity (de Kloet et al., 2007). The decrease in binding affinity and glucocorticoid sensitivity was also observed in an inflammatory state or due to the action of inflammatory cytokines (Ysrraelit et al., 2008). Such abnormalities of GR function were demonstrated in in vitro studies of T cells incubated with a combination of IL‐2 and IL‐4, Il-13 (Almawi et al., 1991), IL‐1β, IL‐6, and interferon (IFN)‐γ (Kam et al., 1993) and in sepsis (Molijn et al., 1995). These results suggest that cytokines produced during an inflammatory response may induce GR resistance in relevant cell types by direct effects on the GR, thereby providing an additional pathway by which the immune system can influence the HPA axis (Pariante et al., 1999).

With that, among the factors contributing to the inconsistency of the data and contradiction in results may be the variations in the inflammatory syndrome’s intensity/severity, which could be different in the abovementioned studies and even in different time-points of each study. The dynamic pattern of the inflammatory reaction and, therefore, its action was well characterized by the results of GJ Molijn et al. (1995), were the increased sensitivity of the peripheral mononuclear cells to dexamethasone during the period of sepsis have changed and normalized during the ensuing period of clinical recovery of those patients (Molijn et al., 1995).

Another mechanism of inflammation’s action on the GR receptor’s functions includes the inhibition of GR translocation and GR-mediated gene transcription and inducing the up-regulation of the cytosolic receptors (Pariante et al., 1999). The changes in the GR isoforms ratio can be responsible for glucocorticoid resistance as well. GR gene encodes two protein isoforms: a cytoplasmic alpha form (GRα), which binds hormone, translocates to the nucleus, and regulates gene transcription, and a nuclear-localized beta isoform (GRβ), which does not bind known ligands and attenuates GRα action (Kino et al., 2009). The GRβ isoform has been shown to have a dominant-negative effect on GRα‐induced transcriptional activity (Hoffman et al., 2015). Studies examining GR isoforms have shown an increase in both GRα and GRβ and a concomitant decrease in the GRα: GRβ ratio in inflammatory states (Hoffman et al., 2015; Longui et al., 2000; Webster, Oakley, Jewell, & Cidlowski, 2001) and depression (Carvalho et al., 2014). The accumulation of GRb isoform makes it an attractive candidate to explain the appearance of glucocorticoid resistance due to the action of inflammatory cytokines (Webster, Oakley, Jewell, & Cidlowski, 2001).

We should also note the possibility of triggering GR resistance by glucose, which could be mediated through both enhancing acetylation (via, among others, regulation of essential clock genes such as Per) and hindering deacetylation of GR (through possible regulation of sirtuin activity) (Kassi & Papavassiliou, 2012).

Moreover, the molecular mechanisms of GR resistance are very diverse and may involve also the changes in epigenetic modification’s patterns and components of the ultra-short negative loop of GC signaling in cells (Merkulov et al., 2017).

Substrate deficiency

Stress is known to influence adrenal gland morphology and function [reviewed in Berger et al., 2019]. Functional and structural signs of adrenal cortex degeneration were observed in PTSD, including decreased plasma concentration of corticosterone, decreased weight of adrenal glands, reduced thickness of the fasciculate zone, and hydropic degeneration of adrenal gland cells (Manukhina et al., 2018). The described stress-induced changes in the adrenal morphology could affect the synthesis of cortisol as well (Arlt & Stewart, 2005). About 80% of circulating cortisol is derived from plasma cholesterol, the remaining 20% is synthesized in situ from acetate and other precursors, while the high-density lipoprotein (HDL) is the preferred cholesterol source of the steroidogenic substrate in the adrenal gland (Yaguchi et al., 1998). HDL is substantially reduced in conditions, accompanied by the inflammatory reaction, including myocardial infarction, sepsis, and burns (Marik, 2007). Thus, in severe sepsis, lipoprotein concentrations rapidly change and can be reduced to 50% of recovery concentrations with the pattern of early rapid decline to be found primarily in the HDL (Marik, 2007).

The decrease in HDL is revealed not only in the abovementioned diseases, but also in patients with PTSD and depression as well [reviewed in Levine et al., 2014]. Thus, patients with full PTSD had lower HDL-C (Känel et al., 2010) and higher prevalence of HDL <1.0 mmol/l and TG >2.3 mmol/l (Walczewska et al., 2011) than patients without PTSD. Moreover, HDL-C levels were inversely associated with the severity of disease: the PTSD total symptoms, reeexperiencing symptoms, and avoidance symptoms (Känel et al., 2010) and the higher serum total cholesterol was associated with lower odds for having suicidal ideation, clinically significant aggression, and depressive symptoms in PTSD (Vilibić et al., 2014).

Finally, the role of substrate deficiency as a cause of adrenal insufficiency was confirmed in the study which demonstrated that HDL was the sole predictor of cortisol response in critically ill patients, associated with an attenuated response to ACTH (van der Voort et al., 2003). Thus, substrate deficiency due to the action of inflammatory cytokines (Jäättelä et al., 1991) in PTSD may contribute to the low GS levels.

MAO-A activity

MAO-A is a key enzyme in the degradation of biogenic amines such as serotonin and dopamine, and the changes in its activity in stress, depression, and PTSD were studied intensively over the last decades.

Glucocorticoid enhances monoamine oxidase A gene expression by 1) regulation of R1 translocation; 2) direct interaction of the GR with the third glucocorticoid/androgen response element; and 3) indirect interaction of GR with the Sp1 or R1 transcription factor on Sp1-binding sites of the MAO-A promoter (Manoli et al., 2005; Ou et al., 2006). Chronic stress and glucocorticoid exposures lasting 24 h or longer have been associated with greater MAO-A synthesis, levels, and activity (Soliman et al., 2012). It is of interest, that dexamethasone was more effective in activating MAO-A gene expression upon 24 h or longer time treatment but not 12 h (Ou et al., 2006). Moreover, continuous glucocorticoid administration over 26 d caused a 3-fold increase in frontal/parietal cortex MAO-A activity in rats (Slotkin et al., 1998), and chronic stress led to 2–3 times increased MAO-A-mRNA levels in the raphe nucleus of CBA/Lac mice (Filipenko et al., 2002). Similar changes were observed in depression (reviewed in Higuchi et al., 2017): depressed patients exhibited lower MAOA methylation than healthy controls. Moreover, MAO-A densities in several brain regions (e.g. prefrontal cortex, hippocampus, and midbrain) were higher in patients with depression even in the recovery phase and were associated with the recurrence of depressive symptoms (Meyer et al., 2009). On the contrary, a highly consistent relationship between acute stressors and glucocorticoid administration and decreased MAO-A binding, activity, and protein levels was revealed (Soliman et al., 2012). Exacerbation period in PTSD decreases MAO activity, thereby increasing the availability of catecholamines and the hypermethylation of 3 CpGs in the MAOA gene exonI/intronI region (Ziegler et al., 2018).

The inflammatory reaction, via pro-inflammatory cytokines, modulates the MAO-A activity as well. MAO-A expression is suppressed by the IL-6 signaling (Huang et al., 2012), while the inhibition of IL-6R signaling or IL-6R siRNA increased MAO-A activity (Bharti et al., 2018). With that, TNF‐α increases the Sp1 expression that in turn activates MAOA gene transcription (Gupta et al., 2015) and systemic LPS administration leads to longer-lasting changes in inhibitory network function and increase in MAO-A and ACh-E activities responsible for reduced neuromodulator actions (Ming et al., 2015).

Inflammation, CNS and PTSD

Fundamentally, there are two points of view on the mechanism of inflammatory reaction’s influence on CNS. From one point of view, in conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, glia and other brain immune cells change their morphology and functioning and secrete high levels of pro-inflammatory cytokines and prostaglandins, which disrupts the delicate balance needed for the neurophysiological actions of immune processes and produces direct detrimental effects (Yirmiya & Goshen, 2011). In this case, the endogenous IL-1 plays a critical role in HPA axis activation after stress (Goshen et al., 2003). It is produced by ameboid microglia, astrocytes, brain oligodendrocytes, while its receptors are shown to be highly concentrated in the dentate gyrus, in the choroid plexus at various levels of the brain, in the pituitary and the meninges (Ban et al., 1991). IL-1R mRNA was found in the hippocampus, choroid plexus, cerebellum, and in high levels in the endothelium of postcapillary venules and glial cells surrounding arterioles throughout the brain (Wong & Licinio, 1994), and, which is important, interleukin-1 type I receptor is expressed in human hypothalamus (Hammond et al., 1999). That is why the production of brain IL-1 is an important link in stress-induced activation of the HPA axis and secretion of glucocorticoids, which mediate the effects of stress on memory functioning and neural plasticity, exerting beneficial effects at low levels and detrimental effects at high levels (Goshen & Yirmiya, 2009).

Other researchers are focusing on the blood-derived cytokines. During the systemic immune challenge, the organum vasculosum laminae terminalis with its dense vascularization by fenestrated capillaries lacking blood–brain barrier (BBB) function allows direct access of circulating pyrogens to brain tissue located in close vicinity to the preoptic area of the hypothalamus (Ott et al., 2010). Moreover, it was shown, that interleukins could be transported from blood to brain across the BBB by a saturable system (Gutierrez et al., 1994). While the amount of blood-borne cytokines entering the brain is modest, it is comparable to that of other water-soluble compounds, known to cross the BBB in sufficient amounts to affect brain function (Banks et al., 1995).

Blood-derived cytokines also act on the CNS via endothelial cells, which are a critical component of the BBB. These cells are innately programed to respond to a myriad of inflammatory cytokines or other danger signals and their activation to produce local inflammatory mediators (including IL-1) contributes to the CNS activation in inflammatory conditions as well (O’Carroll et al., 2015). Moreover, brain endothelial cells are the major source of prostaglandin E2 under the inflammatory state, which influences the central neuronal and HPA axis activity (Matsumura & Kobayashi, 2004).

Generally, we fully agree with H. Hori and Kim (2019) that a better understanding of the causes and consequences of the altered inflammatory system will aid in developing biologically oriented diagnostics and treatment for PTSD (Hori & Kim, 2019).

Conclusion

The described state of the biochemical changes, characterized by the low cortisol levels, GR resistance and the signs of the persistent inflammation (higher levels of IL-6) could be observed not only in PTSD but in coronary heart diseases and systemic chronic inflammatory diseases (RA) as well (Nikkheslat et al., 2015; Pariante, 2017; Straub & Cutolo, 2016). Thus, the depressed patients with coronary heart disease have higher inflammation (higher IL-6 mRNA and higher levels of c-reactive protein) together with reduced expression of GR mRNA, which was associated with HPA axis hypoactivity (Nikkheslat et al., 2015; Pariante, 2017).

The similarity of the clinical features of the distinct diseases makes one think about the common links in their pathogenesis and the inflammatory reaction could serve as one of these links. With that, there are several studies of Danese et al. (2007–2009), which have direct associations with PTSD studies of R Yehuda (2005–2007). Thus, it was shown that the increased inflammation was present not only in subjects who were depressed and had a history of childhood maltreatment but also in those who had experienced maltreatment but were not depressed (Danese et al., 2007, 2008, 2009). Together, these findings indicate that the increased inflammation is a “biological scar” of the early exposure to high levels of stress (or possibly directly to inflammation), early in childhood or even in utero (Pariante, 2017; Plant et al., 2016; Preez et al., 2016), that leads to the typical picture of PTSD with hypocortisolemia and low-grade inflammation.

Author contribution

All authors contributed to the study concept and the study design. Alexey Sarapultsev, Eliyahu Dremencov, Petr Sarapultsev, Maria Komelkova, Olga Tselikman, and Vadim Tselikman drafted the manuscript, Petr Sarapultsev and Eliyahu Dremencov provided critical revisions. Maria Komelkova created the artwork. All authors approved the final version of the manuscript for submission.

Disclosure statement

The authors declare no conflict of interest and no financial interest in the publication of this manuscript.

Additional information

Funding

This work was supported by the Ministry of Science and Higher Education of Russian Federation (grants AAAA-A18-118020690020-1 and 17.7255.2017/8.9) and by Slovak Research and Development Agency (Grant APVV-15-0388).

Notes on contributors

Alexey Sarapultsev

Alexey Sarapultsev, MD (Ural State Medical Academy, Ekaterinburg, Russia, 2005), PhD (Tymen State Medical Academy, Tymen, Russia, 2010), ScD (Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia, 2019). Senior researcher, Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia.

Petr Sarapultsev

Petr Sarapultsev, MD (Sverdlovsk State Medical Institute, Sverdlovsk, USSR, 1971), PhD (Sverdlovsk State Medical Institute, Sverdlovsk, USSR, 1983), ScD (Sverdlovsk State Medical Institute, Sverdlovsk, Russia, 1993), Professor (1996). Principal researcher, Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia.

Eliyahu Dremencov

Eliyahu Dremencov, MMedSc (Hebrew University, Jerusalem, Israel, 2000), PhD (Bar-Ilan University, Israel, 2004) is an Independent Research Fellow in the Institute of Molecular Physiology and Genetics (IMPG), Center for Biosciences, and Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Science (since 2013), Head of the IMPG Neuropharmacological Laboratory (2016-), Head of the IMPG (2018-)

Maria Komelkova

Maria Komelkova, MD (Chelyabinsk state University, Chelyabinsk, Russia, 2005), PhD (South-Ural State Medical University, Chelyabinsk, Russia, 2015). Senior researcher, Institute of Immunology and Physiology, Ural Division of the Russian Academy of Sciences, Ekaterinburg, Russia; Senior researcher, School of Medical Biology in the South Ural State University

Olga Tseilikman

Olga Tseilikman, PhD (2001, South Ural State Medical University, Chelyabinsk, Russia), DSc (2005, Omsk State Medical University, Omsk, Russia), is a Professor in the School of Medical Biology, South Ural State University, Chelyabinsk, Russia.

Vadim Tseilikman

Vadim Tseilikman, MSc Chelyabinsk State Pedagogical University, Chelyabinsk Russia, 1982), PhD (Siberian State Medical University, Tomsk, Russia, 1992), DSc (Institute of General Pathology and Pathological Physiology, Moscow, Russia, 1999). Director of School of Medical Biology in the South Ural State University (2017-).