Stress and Inflammation

Stress has been described by the World Health Organization as the “health epidemic of the 21st century” and causes immense healthcare costs worldwide (Fink 2016). But how can stress be defined in the first place? First of all, stress represents the (non-specific) reaction of the body to a demand (Fink 2016). Our daily lives within complex social structures involve many such demands (some unforeseen), which we must manage. Throughout our entire lifespan, we must react to situations that, in the worst case, threaten our health or survival (Rohleder 2019). The interpretation of stressors in our body is the responsibility of the brain, particularly the amygdala. Furthermore, other neural structures such as the thalamus, hypothalamus, brainstem nuclei (e.g., locus coeruleus), the neocortex, and the limbic system play important roles in the perception of and reaction to stress (Fink 2016). Our organism possesses various stress systems that modulate adjustments to the homeostatic state, either to appropriately manage demands or to actually ensure survival in threatening situations. Thus, while the body’s own stress systems are important for navigating our environment and reacting appropriately to threats or demands, they also mediate inflammatory mechanisms. In cases of persistent stress, persistent low-grade inflammation is also caused, which results in serious long-term health impairments, as described in detail in the concept of allostatic load (McEwen and Stellar 1993).Stress Systems

1. Sympathetic branch of the autonomous nervous system (ANS) – fight-or-flight response

The ANS consists of the antagonists: the sympathetic and parasympathetic nervous systems. While the sympathetic system modulates stress reactions, the parasympathetic system is responsible for the state of relaxation. Stressors are transmitted to the brain via the nerves of the sympathetic trunk in the spinal cord and processed there. This is followed by a secretion of catecholamines, primarily adrenaline and noradrenaline. This leads to physiological adaptations, such as an increase in blood sugar levels, blood pressure, and heart rate, as well as a stimulation of the inflammatory response with an increase in inflammatory cytokines in the blood (Sapolsky et al. 2000).  

2. Hypothalamic-pituitary-adrenal axis (HPA axis) with the end hormone cortisol

Parallel to the very rapid adaptation reaction by the sympathetic nervous system, the amygdala informs the hypothalamus about the stress situation. The hypothalamus then releases hormonal messengers, including corticotropin-releasing hormone, which leads to a release of adrenocorticotropin (ACTH) in the pituitary gland. The ACTH reaches the adrenal cortex via the blood, which then reacts with cortisol secretion. The hypothalamic-pituitary-adrenal axis is thus also able to influence blood pressure or immune mechanisms. Together, both stress systems ensure that our body receives more oxygen and energy to act quickly (Sapolsky et al. 2000).  How does acute stress differ from chronic stress?Upon the first exposure to a stressor, the processes mentioned above take place, enabling us to deal with the stress situation. In the best-case scenario, the parasympathetic nervous system reverses all physiological adaptations and returns the organism to a state of homeostasis.  However, if the psychosocial stress situation repeats frequently, as is the case with workplace stress, caring for relatives, or discrimination, it becomes a chronic stressor. There is sufficient evidence that chronic stress experiences are linked to a variety of diseases, including cardiovascular disease, insulin insensitivity, and cancer (Cohen et al. 2012). Furthermore, changes in the HPA axis in chronically stressed individuals lead to modulated basal activity, a loss of circadian rhythm, and lower total cortisol secretion during the day (Miller et al. 2007). Research also shows that inflammatory processes play a central role in the link between exposure to chronic life stress and such diseases (Rohleder 2019). While we now better understand the effects of acute and chronic stress on inflammatory mechanisms, there is a significant gap in our understanding of the transition phase between acute and chronic stress. This leads to the key question: at what point do we refer to repeated stressors as chronic stress? Nicolas Rohleder addressed this question in a descriptive review, which will be presented below.  How does stress affect human health and longevity?As described in more detail above, the adaptation reactions to acute and chronic stress through the ANS and the HPA axis are well documented (McEwen and Stellar 1993). However, the international research community has not yet succeeded in establishing prospective links between changes in the two stress systems and the pathogenesis of diseases. This is because the end hormones of the ANS and the HPA axis do not have strong pathophysiological effects on their own, but rather modulate other complex systems. These systems influence each other with varying efficiency and with different effects on downstream pathophysiological processes (Cohen et al. 2012, Miller et al. 2002). Quantitative research methods find it difficult to capture this range of metrics, and research is still far from understanding the entire signaling cascade from the central nervous system through all stress-sensitive systems to all potentially pathophysiologically relevant systems in the periphery of the body. Therefore, focus is placed more on the body’s own systems that are already known to be associated with stress reactions and have been proven to play an important role in the development of diseases. The most important system here is the innate immune system with its inflammatory reactions.  Within this system, there is the phenomenon of systemic, low-grade inflammation, which must be strictly separated from inflammation triggered by infections or injuries.What is systemic, low-grade inflammation?Systemic, low-grade inflammation does not manifest locally but is generalized and to a much lesser extent than, for example, acute infections. Furthermore, it is usually a long-term phenomenon, even if temporary changes occur after acute stress. There is no obvious trigger for this type of inflammation (Black 2002), yet it is an important indicator in predicting morbidity/mortality and has been identified as a key factor in cardiovascular disease, cancer, diabetes, and age-related diseases such as Alzheimer’s (Couzin-Frankel 2010). The following parameters are considered indicators of systemic inflammatory activity (McInnis et al. 2014, Rohleder et al. 2007):

• Plasma concentration of pro-inflammatory cytokines (IL-6, IL-1 beta, TNF-alpha)
• C-reactive protein (CRP)

Furthermore, our understanding in stress research is beginning to include mitochondrial health (Picard and Ewen 2018) and telomere shortening (Epel et al. 2004). Stimulation of systemic inflammatory reactions by acute stress The inflammatory reaction following acute stress is activated by demands from the physical environment as well as from the social environment (Black 2002). Acute stress has manifold effects on various components of the immune system, including the number and composition of circulating leukocytes as well as cytokine synthesis (Segerstrom and Miller 2004). Various reviews and meta-analyses have concluded that acute stress leads to a significant increase in IL-1 beta, IL-6, and TNF-alpha, and found no stress-related increase in CRP (Marsland et al. 2017, Steptoe et al. 2007). Furthermore, the meta-analysis by Marsland and colleagues showed that these results are independent of age and gender. Further associations between stress reactions and inflammatory markers:

• Depressive symptoms
  • Increase inflammatory markers (IL-6, TNF-alpha, and CRP) (Pace et al. 2009)
• Character traits and anthropometric data
  • Increased inflammatory mediators in cases of low self-esteem (O’Donnell et al. 2008), high hostility (Brydon et al. 2010), and in lonely women (Hackett et al. 2012)
• Low socio-economic status (Brydon et al. 2004), work stress (Hamer et al. 2006), low self-compassion (Breines et al. 2014), low self-reflection (Woody et al. 2016), and poor sleep (Heffner et al. 2012) can also lead to higher inflammatory stress reactions
• Physical fitness (Hamer and Steptoe 2007) and a low body fat percentage (McInnis et al. 2014), on the other hand, lead to a lower IL-6 stress level

Systemic, low-grade inflammation in chronic stress. A stressor is considered chronic if unfavorable psychosocial conditions persist over a longer period. Chronic stress can take many different forms, which are not the same for all individuals and vary significantly in terms of duration and intensity (Segerstrom and Miller 2004).  As already described in the section “How does acute stress differ from chronic stress?”, chronic stress is associated with various diseases, including depression (Slavich and Irwin 2014) and cardiovascular diseases (Kivimäki et al. 2006). Furthermore, there are correlations with other diseases that are widespread in our modern societies. The international research community suspects that systemic low-grade inflammation plays a decisive role in the pathogenesis of all these diseases (Glaser and Kiecolt-Glaser 2005, Segerstrom and Miller 2004, Slavich and Irwin 2014). The best-studied cohort with chronic stress consists of individuals who care for relatives. Cross-sectional or longitudinal data are collected for this group and compared with those of non-caregivers. As a caregiver with high stress levels, the risk of cardiovascular disease increases (Haley et al. 2010), as does the risk of early death (Schulz and Beach 1999). Low-grade inflammation again seems to play an important role, as several cross-sectional studies have found. In particular, plasma levels of interleukin-6 were significantly elevated in caregivers with chronic stress in these studies (Gouin et al. 2012, von Känel et al. 2006, Lutgendorf et al. 1999, Mausbach et al. 2011). Data from longitudinal studies indicated that IL-6 concentration increased more sharply over a six-year period in older caregivers of Alzheimer’s patients than in control subjects (Kiecolt-Glaser et al. 2003) and that the duration of care was associated with higher CRP levels (von Känel et al. 2012). However, both occupational stress on one hand and unemployment on the other lead to changes in inflammation-mediating parameters. For example, one study showed that unemployment led to higher IL-6 and CRP values (Hintikka et al. 2009). Higher inflammation values as a result of increased stress levels were observed, for example, in teachers (von Känel et al. 2008).  It is now considered certain that experiences (positive or negative) in early childhood are formative for the psyche and body for the entire lifespan. Even the mother’s diet during pregnancy influences the epigenetic programming of the embryo, as epidemiological studies prove (Krauss-Etschmann et al. 2010). Negative experiences during critical early development windows can be seen as a form of chronic stress. A low socioeconomic status and the associated limitations correlate with higher systemic inflammatory activity in adolescence and adulthood. Miller and colleagues have proven that there is an increased expression of inflammatory genes in circulating immune cells in adulthood (Miller et al. 2009). Analogously, this relationship also seems to apply to plasma concentrations of IL-6 and CRP (Packard et al. 2011). If more intense negative experiences such as abuse, neglect, and/or trauma occur in early childhood, the effects mentioned above are intensified. In a high-quality meta-analysis from 2016 with more than 15,000 subjects, strong links were established between plasma levels of the most important inflammatory mediators (IL-6, CRP, and TNF-alpha) and childhood trauma. These strong associations appear to persist into late adulthood and are associated with a higher risk of physical or mental illness. The analysis also showed that childhood trauma contributes to a pro-inflammatory state in adulthood, with specific inflammatory profiles depending on the specific type of trauma (Baumeister et al. 2016). Chronic stress can, as already shown, take many different forms and manifest in different phases of life. The effects on inflammatory activity are well documented, with one’s own experience or burden from stress playing a role in the changes of inflammatory mediators. One’s own perception and cognitive evaluation of stressors thus have different effects on inflammatory activity (Rohleder 2019). Can the increased activity of inflammatory mediators in acute or chronic stress be reversed? A high-quality RCT study from 2013 examined the effect of yogic meditation on the activity of inflammatory transcription control pathways that influence the gene expression of immune cells. An 8-week meditation intervention in family caregivers of dementia patients led to a downregulation of pro-inflammatory cytokines, while immunoglobulin-related transcripts were upregulated. This shows that a short yogic meditation can reverse and lower the increased activity of inflammatory mediators after stress exposure (Black et al. 2013). In another study, similar effects were achieved with a stress management intervention (Laudenslager et al. 2016).At what point do repeated, acute stressors become chronic stress?Approaching this question is scientifically problematic, as experimental laboratory studies lack external validity because they always involve an artificial stress situation. Thus, the observed reactions cannot be transferred 1:1 to real everyday stress.  The concept of stressful event sequences best describes the time span or phase between acute and chronic stress. It is based on the assumption that there is a transition phase between an initial, acute exposure to a new stressor and the subsequent development through repeated exposure into something that could be called chronic stress (Rohleder 2019). The few available studies on repeated stress suggest that the way in which repeated acute stress turns into long-term changes varies. Future studies must further close the knowledge gap in the transition phase from acute to chronic stress by examining (long-term) habituation effects of stress reactions of the inflammatory system in more detail.  Also check out the scientifically proven effective tips for stress and inflammation in my new book: More about the book. Literature: Baumeister D, Akhtar R, Ciufolini S, et al. Childhood trauma and adulthood inflammation: A meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry. 2016;21(5):642-649. Black DS, Cole SW, Irwin MR, et al. Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Psychoneuroendocrinology. 2013;38(3):348-355. Black PH. Stress and the inflammatory response: A review of neurogenic inflammation. Brain Behav Immun. 2002;16(6):622-653. Breines JG, Thoma M V, Gianferante D, et al. Self-compassion as a predictor of interleukin-6 response to acute psychosocial stress. Brain Behav Immun. 2014;37:109-114. Brydon L, Edwards S, Mohamed-Ali V, et al. Socioeconomic status and stress-induced increases in interleukin-6. Brain Behav Immun. 2004;18(3):281-290. Brydon L, Strike PC, Bhattacharyya MR, et al. Hostility and physiological responses to laboratory stress in acute coronary syndrome patients. J Psychosom Res. 2010;68(2):109-116. Cohen S, Janicki-Deverts D, Doyle WJ, et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci. 2012;109(16):5995 LP – 5999. Couzin-Frankel J. Inflammation Bares a Dark Side. Science (80- ). 2010;330(6011):1621. Epel ES, Blackburn EH, Lin J, et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 2004;101(49):17312 LP – 17315. Fink G. Outlined: Lessons from Anxiety. Stress Concepts Cogn Emot Behav. 2016;1(April):3-11. Glaser R, Kiecolt-Glaser JK. Implications for Health. Nat Rev Immunol. 2005;5(March):243-251. Gouin J-P, Glaser R, Malarkey WB, et al. Chronic stress, daily stressors, and circulating inflammatory markers. Heal Psychol. 2012;31(2):264-268 doi:10.1037/a0025536. Hackett RA, Hamer M, Endrighi R, et al. Loneliness and stress-related inflammatory and neuroendocrine responses in older men and women. Psychoneuroendocrinology. 2012;37(11):1801-1809. Haley WE, Roth DL, Howard G, et al. Caregiving strain and estimated risk for stroke and coronary heart disease among spouse caregivers: differential effects by race and sex. Stroke. 2010;41(2):331-336. Hamer M, Steptoe A. Association between physical fitness, parasympathetic control, and proinflammatory responses to mental stress. Psychosom Med. 2007;69(7):660-666. Hamer M, Williams E, Vuonovirta R, et al. The Effects of Effort-Reward Imbalance on Inflammatory and Cardiovascular Responses to Mental Stress. Psychosom Med. 2006;68(3). Heffner KL, Ng HM, Suhr JA, et al. Sleep Disturbance and Older Adults’ Inflammatory Responses to Acute Stress. Am J Geriatr Psychiatry. 2012;20(9):744-752. Hintikka J, Lehto SM, Niskanen L, et al. Unemployment and ill health: a connection through inflammation? BMC Public Health. 2009;9(1):1-6. von Känel R, Mills PJ, Mausbach BT, et al. Effect of Alzheimer Caregiving on Circulating Levels of C-Reactive Protein and Other Biomarkers Relevant to Cardiovascular Disease Risk: A Longitudinal Study. Gerontology. 2012;58(4):354-365. von Känel R, Bellingrath S, Kudielka BM. Association between burnout and circulating levels of pro- and anti-inflammatory cytokines in schoolteachers. J Psychosom Res. 2008;65(1):51-59. von Känel R, Dimsdale JE, Mills PJ, et al. Effect of Alzheimer Caregiving Stress and Age on Frailty Markers Interleukin-6, C-Reactive Protein, and D-Dimer. Journals Gerontol Ser A. 2006;61(9):963-969. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, et al. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci. 2003;100(15):9090-9095. Kivimäki M, Virtanen M, Elovainio M, et al. Work stress in the etiology of coronary heart disease – A meta-analysis. Scand J Work Environ Heal. 2006;32(6):431-442. Krauss-Etschmann S, Aneja MK, Schulz N. Environmentally induced early imprinting of asthma and epigenetics. Monatsschr Kinderheilkd. 2010;158(2):142-148. Laudenslager ML, Simoneau TL, Philips S, et al. A randomized controlled pilot study of inflammatory gene expression in response to a stress management intervention for stem cell transplant caregivers. J Behav Med. 2016;39(2):346-354. Lutgendorf SK, Garand L, Buckwalter KC, et al. Life Stress, Mood Disturbance, and Elevated Interleukin-6 in Healthy Older Women. Journals Gerontol Ser A. 1999;54(9):M434-M439. Marsland AL, Walsh C, Lockwood K, et al. The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis. Brain Behav Immun. 2017;64:208-219. Mausbach BT, von Känel R, Roepke SK, et al. Self-Efficacy Buffers the Relationship Between Dementia Caregiving Stress and Circulating Concentrations of the Proinflammatory Cytokine Interleukin-6. Am J Geriatr Psychiatry. 2011;19(1):64-71. McEwen BS, Stellar E. Stress and the Individual: Mechanisms Leading to Disease. Arch Intern Med. 1993;153(18):2093-2101. McInnis CM, Thoma M V, Gianferante D, et al. Measures of adiposity predict interleukin-6 responses to repeated psychosocial stress. Brain Behav Immun. 2014;42:33-40. Miller GE, Chen E, Fok AK, et al. Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling. Proc Natl Acad Sci. 2009;106(34):14716 LP – 14721. Miller GE, Chen E, Zhou ES. If it goes up, must it come down? Chronic stress and the hypothalamic-pituitary-adrenocortical axis in humans. Psychol Bull. 2007;133(1):25-45 doi:10.1037/0033-2909.133.1.25. Miller GE, Cohen S, Ritchey AK. Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model. Heal Psychol. 2002;21(6):531-541 doi:10.1037/0278-6133.21.6.531. O’Donnell K, Brydon L, Wright CE, et al. Self-esteem levels and cardiovascular and inflammatory responses to acute stress. Brain Behav Immun. 2008;22(8):1241-1247. Pace TWW, Negi LT, Adame DD, et al. Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to psychosocial stress. Psychoneuroendocrinology. 2009;34(1):87-98. Packard CJ, Bezlyak V, McLean JS, et al. Early life socioeconomic adversity is associated in adult life with chronic inflammation, carotid atherosclerosis, poorer lung function and decreased cognitive performance: a cross-sectional, population-based study. BMC Public Health. 2011;11(1):1-16. Picard M, McEwen BS. Psychological Stress and Mitochondria: A Conceptual Framework. Psychosom Med. 2018;80(2). Rohleder N. Stress and inflammation – The need to address the gap in the transition between acute and chronic stress effects. Psychoneuroendocrinology. 2019;105(August 2018):164-171. Rohleder N, Beulen SE, Chen E, et al. Stress on the dance floor: The cortisol stress response to social-evaluative threat in competitive ballroom dancers. Personal Soc Psychol Bull. 2007;33(1):69-84. Sapolsky RM, Romero LM, Munck AU. How Do Glucocorticoids Influence Stress Responses? Integrating Permissive, Suppressive, Stimulatory, and Preparative Actions*. Endocr Rev. 2000;21(1):55-89. Schulz R, Beach SR. Caregiving as a risk factor for mortality: the Caregiver Health Effects Study. Jama. 1999;282(23):2215-2219. Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130(4):601. Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. Psychol Bull. 2014;140(3):774-815 doi:10.1037/a0035302. Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: A review and meta-analysis. Brain Behav Immun. 2007;21(7):901-912. Woody A, Figueroa WS, Benencia F, et al. Trait reflection predicts interleukin-6 response to a social-evaluative stressor. Brain Behav Immun. 2016;52:27-31