Stress and the inflammatory response: A review of neurogenic inflammation

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Abstract

The subject of neuroinflammation is reviewed. In response to psychological stress or certain physical stressors, an inflammatory process may occur by release of neuropeptides, especially Substance P (SP), or other inflammatory mediators, from sensory nerves and the activation of mast cells or other inflammatory cells. Central neuropeptides, particularly corticosteroid releasing factor (CRF), and perhaps SP as well, initiate a systemic stress response by activation of neuroendocrinological pathways such as the sympathetic nervous system, hypothalamic pituitary axis, and the renin angiotensin system, with the release of the stress hormones (i.e., catecholamines, corticosteroids, growth hormone, glucagons, and renin). These, together with cytokines induced by stress, initiate the acute phase response (APR) and the induction of acute phase proteins, essential mediators of inflammation. Central nervous system norepinephrine may also induce the APR perhaps by macrophage activation and cytokine release. The increase in lipids with stress may also be a factor in macrophage activation, as may lipopolysaccharide which, I postulate, induces cytokines from hepatic Kupffer cells, subsequent to an enhanced absorption from the gastrointestinal tract during psychologic stress. The brain may initiate or inhibit the inflammatory process. The inflammatory response is contained within the psychological stress response which evolved later. Moreover, the same neuropeptides (i.e., CRF and possibly SP as well) mediate both stress and inflammation. Cytokines evoked by either a stress or inflammatory response may utilize similar somatosensory pathways to signal the brain. Other instances whereby stress may induce inflammatory changes are reviewed. I postulate that repeated episodes of acute or chronic psychogenic stress may produce chronic inflammatory changes which may result in atherosclerosis in the arteries or chronic inflammatory changes in other organs as well.

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.

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