Stress and the inflammatory response: A review of neurogenic inflammation
Introduction
There is now incontrovertible evidence that the nervous and immune systems interact bidirectionally i.e., the central nervous system (CNS) by means of its neuropeptides, neurohormones, and neurotransmitters interacts with the immune system which, in turn, feeds back to the brain which then induces changes both in behavior (sickness response) and in the immune system as well (see Black, 1994; Chrousos & Gold, 1992; Maier & Watkins, 1998 for reviews). It is also known that nerves which contain inflammatory neuropeptides may participate in a local inflammatory reaction in response to infection, toxins or trauma, a process called neurogenic inflammation. What is less appreciated, is the fact that the CNS has the capacity to both produce as well as modulate general inflammatory reactions, not only in response to infection, trauma, and tissue damage but in response to stress as well (Black & Berman, 1999).
I will review the evidence that stress alone can cause an inflammatory response and that repeated or chronic episodes of stress may result in inflammatory diseases. Thus, hormonal changes which characterize the stress response may induce an inflammatory process. The major stress hormones (e.g., the catecholamines, corticosteroids, renin, glucagon, and growth hormone) can induce an acute phase response (APR) which is similar to the response elicited when an organism reacts to an invading microorganism, or sustains trauma and tissue injury. Stress may also activate primary sensory neurons similar to the response elicited by a toxin affecting the nerve as in neurogenic inflammation. In this paper, I shall review the current status of neuroinflammation. I shall also emphasize that a stress-induced APR may result in an inflammatory process. I shall refer frequently to atherosclerosis since it is now believed to result from a chronic inflammatory process. Stress may be a co-factor in the etiology of this process; however, in a certain number of cases without any of the other known causal co-factors (≈40%), stress may be the only risk factor and may therefore play an even larger role in the pathogenesis of this disease (Leon, Chan, Volteas, Labropoulos, & Nicolaides, 1993; Matthews et al., 1998; Rozanski, Blumenthal, & Kaplan, 1999; Ross, 1999; Black & Garbutt, 2002).
Section snippets
Neurobiology of stress
Stress can be defined as a state of threatened homeostasis provoked by a psychological, environmental, or physiologic stressor (Chrousos & Gold, 1992; Peterson, Chan, & Molitor, 1991). One can also define stress as a stimulus, either internal or external, that activates the hypothalamic pituitary adrenal axis (HPA) and the sympathetic nervous system (SNS), resulting in a physiological change or adaptation so that the organism can deal with the threat (Maier & Watkins, 1998). In addition to
Inflammation and the stress response
Inflammatory stimuli may also lead to activation of the HPA axis. The inflammatory response is the most primitive of protective mechanisms; rudiments of it existed before the development of the nervous system (Reichlin, 1999). The stress response evolved from and is intricately linked to the inflammatory response. Both are highly conserved over time and species (Maier & Watkins, 1998). An important inflammatory stimulus is lipopolysaccharide (LPS; endotoxin), which is contained in the cell
Association of nerves with an inflammatory process
Nerves, both somatic and autonomic, are intimately associated with inflammatory cells; this is especially true of mast cells which resemble nerve cells in many respects (Purcell & Atterwill, 1995). Indeed, the embryologic development of the sympathetic nervous system parallels the development of neurogenic inflammation in several species examined, and post-natal development of neurogenic inflammation in the rat parallels the development of the SNS (Gonzales, Coderre, Sherbourne, & Levine, 1991
Primary afferent “C” sensory nerve
Most of the evidence for neurogenic inflammation has been derived from studies of the primary, unmyelinated sensory nerve fiber, the “C” fiber (see Baluk, 1997; Wallengren, 1997 for reviews). Stimulation of sensory nerves containing these fibers with an electrical current, mechanically, by heat, or by noxious chemicals such as formalin or mustard oil, or even loose ligation of the sciatic nerve (Daemen et al., 1998), results in antidromic transmission and an ensuing inflammatory response; this
Substance P and other neuropeptides as mediators of stress and inflammation
The association of psychogenic stress with inflammation is strengthened by the fact that certain neuropeptides such as CRF are known to mediate both stress and inflammation. Although other neuropeptides may have similar effects, I will consider the evidence that SP, a known mediator of neurogenic inflammation, may also be involved in the stress response as well as non-neurogenic inflammation. Neurotensin will also be briefly reconsidered.
Stress and glucocorticoids
Glucocorticoids, released during the stress response, are often identified with their powerful anti-inflammatory and immunosuppressive effects which they promote at certain doses. However, corticosteroids are now known to take part in many of the early and essential reactions of the organism to stress including the inflammatory reaction (i.e., to have permissive as well as suppressive effects on inflammation and/or immunity) (McEwen et al., 1997; Munck, Guyre, & Holbrook, 1984; Munck &
Lipoproteins and the APR: Stress and lipoproteins
Psychological stress is associated with increases in lipids including cholesterol, lipoproteins, triglyceride, and free fatty acids (McCann et al., 1995; Munck & Naray-Fejes-Toth, 1994; Stoney, Niaura, Bausserman, & Matacin, 1999). These changes in lipid metabolism are part of the acute phase response. Such changes induced by stress would act to protect the host from toxic components of microorganisms (e.g., LPS). Lipoproteins, as well as their apoproteins bind to the inner or hydrophobic core
Regulation of HPA axis
The HPA axis, one of the most important homeostatic mechanisms that regulate the degree of inflammation (Kapcala, Chautard, & Eskay, 1995), its stimulation by sensory afferents in somatosensory stress (e.g., pain), by cytokines in stress and/or infection, and the essential role of CRF in its stimulation have been discussed (Green et al., 1995; Green et al., 1998; Miao, Benowitz, Heller, & Levine, 1997). In addition to NE and E from the medullary catecholaminergic nuclei, the major stimulants of
Stress and cardiovascular disease
Reference has been made throughout the text that repeated episodes of stress or chronic stress may induce inflammatory changes in blood vessels that may induce or contribute to the progression of atherosclerosis. To summarize, stress, by activating the sympathetic nervous system, the hypothalamic pituitary axis, and the renin angiotensin system, causes the release of various stress hormones and elevated homocysteine (see McCully, 1996; Welch & Loscalzo, 1998 for reviews), which induce a
Stress and inflammation: Interactions and conclusions
In response to psychological stress, an inflammatory process may occur by release of neuropeptides from a sensory nerve and the activation of mast cells. The bradykinin induced synovitis model in rats emphasized the importance of the SNS and the release of inflammatory mediators from the terminals of the PGSN. Neuropeptides, particularly CRF and SP, but perhaps neurotensin as well, also participate in both the mediation of stress individually or together, and as concluded from the experimental
Acknowledgments
The author wishes to acknowledge Lisa Garbutt, a third year medical student, who helped research the paper, and Michelle Villarta, a first year medical student, for invaluable help in the preparation of the manuscript.
References (286)
- et al.
Modulation by adrenergic transmitters of the efferent function of capsaicinsensitive nerves in cardiac tissue
Neuropeptides
(1991) - et al.
Neuropeptides and interleukin-6 in human joint inflammation; relationship betvveen intraarticular substance P and interleukin-6 concentratio ns
Neurosci. Lett.
(1994) Neurogenic inflammation in skin and airvvays
J. Investig. Dermatol. Symp. Proc.
(1997)- et al.
The acute phase response
Immunol. Today
(1994) - et al.
Stress, inflammation and cardiovascular disease
J. Psychosomatic Research
(2002) - et al.
Stress and lipoprotein metabolism: Modulators and mechanisms
Metabolism
(1993) - et al.
Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, cholecystokinin and somatostatin levels in the periaqueductal grey and limbic regions
Neuropeptides
(1994) - et al.
Neuropeptides in sensory neurons
Life Sci.
(1982) - et al.
Anti-platelet activity of beta-adrenergic antagonists: Inhibition of thromboxane synthesis and platelet aggregation in patients receiving long-term propranolol treatment
Lancet
(1981) - et al.
Local oedema and general excitation of cutaneous sensory receptors produced by electrical stimulation of the saphenous nerve in the rat
Pain
(1976)
Epinephrine exacerbates arthritis by an action at presynaptic β2-adrenoceptors
Neuroscience
Prolonged effect of pyschological disturbance on macrophage chemiluminescence in the squirrel monkey
Brain Behav. Immun.
Iron status and risk of cardiovascular disease
Ann. Epidemiol.
Induction of plasma interleukin-6 by circulating adrenaline in the rat
Psychoneuroendocrinology
Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley
J. Neuroimmunol.
Experimental approaches to therapy and prophylaxis for heat stress and heatstroke
Wilderness Environ. Med.
The role of the adrenals in the acute phase response to interleukin-1 and tumor necrosis factor a
J. Surg. Res.
Catecholamine-induced mechanical sensitization of cutaneous nociceptors in the rat
Neurosci. Lett.
Postnatal development of neurogenic inflammation in the rat
Neurosci. Lett.
Modulation of bradykinin-induced plasma extravasation in the rat knee joint by sympathetic cotransmitters
Neuroscience
Further substantiation of a significant role for the sympathetic nervous system in inflammation
Neuroscience
Neurogenic and non-neurogenic mechanisms of plasma extravasation in the rat
Neuroscience
Neuropeptides enhance irritant and allergic contact dermatitis
J. Invest. Dermatol.
Activation of macrophages by neuropeptides
Brain Behav. Immun.
Changes in endotoxin sensitivity in ageing Absorption, elimination and mortality
Mech. Ageing Dev.
An hepatic osmoreceptor mechanism in the rat: Electrophysiological and behavioral Studies
Am. J. Physiol.
Molecular biology of macrophage activation: A pathway whereby psychological factors can potentially affect health
Psychosom. Med.
Adrenergic mechanisms in the control of corticotrophin secretion
J. Endocrinol.
The contribution of the nervous system to inflammation and inflammatory disease
Can. J. Physiol. Pharmacol.
Neurogenic inflammation: With additional discussion of central and perceptual integration of nonneurogenic inflammation
Environ. Health Perspect.
Neurohormonal host defense in endotoxin shock
Ann. N. Y. Acad. Sci.
Atherosclerosis: Basic mechanisms. Oxidation, inflammation, and genetics
Circulation
Substance P primes murine peritoneal macrophages for an augmented proinflammatory cytokine response to lipolysaccharide
Neuroimmunomodulation
Central nervous system-immune system interactions: Pyschoneuroendocrinology of stress and its immune consequences
Antimicrob. Agents Chemother.
Psychoneuroimmunology: Brain and immunity
Sci. Med.
Stress and Inflammation
Cytokines and fever
Ann. N. Y. Acad. Sci.
Adrenal hormones and the regulation of acute phase protein synthesis
Folia Histochem. Cytobiol.
Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin
Nature
Modulation of the release and activity of neuropeptides in the microcirculation
Can. J. Physiol. Pharmacol.
Possible connections between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis
Clin. Sci.
Social inequality in coronary risk: Central obesity and the metabolic syndrome. Evidence from the Whitehall II study
Diabetologia
Neurotransmitter regulation of the hypothalamic corticotropin-releasing hormone neuron
Ann. N. Y. Acad. Sci.
Multiple feedback regulatory loops upon rat hypothalamic corticotropin-releasing hormone secretion Potential clinical implications
J. Clin. Invest.
Differential activation in intestinal epithelial cell expression of Toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease
Infect. Immun.
Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Tolllike receptors
J. Immunol.
Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats
Proc. Natl. Acad. Sci. USA
Acute stress causes mucin release from rat colon: Role of corticotropin releasing factor and mast cells
Am. J. Physiol.
A neurotensin antagonist, SR 48692, inhibits colonic responses to immobilization stress in rats
Proc. Natl. Acad. Sci. USA
Neurokinin-1 (NK-1) receptor is required in Clostridium difficile-induced enteritis
J. Clin. Invest.
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