Innate Immunity: A Balance between Disease and Adaption to Stress

Trends in Molecular Medicine, 2012

Different lines of research have revealed that pathways activated by the endoplasmic reticulum (ER) stress response induce sterile inflammation. When activated, all three sensors of the unfolded protein response (UPR), PERK, IRE1, and ATF6, participate in upregulating inflammatory processes. ER stress in various cells plays an important role in the pathogenesis of several diseases, including obesity, type 2 diabetes, cancer, and intestinal bowel and airway diseases. Moreover, it has been suggested that ER stress-induced inflammation contributes substantially to disease progression. However, this generalization can be challenged at least in the case of cancer. In this review, we emphasize that ER stress can either aid or impede disease progression via inflammatory pathways depending on the cell type, disease stage, and type of ER stressor. Signaling behind ER stress-induced inflammation: from UPR sensors to inflammatory processes Stress on the machinery of the ER can activate various processes, including the signaling pathway of the UPR and the integrated stress response. Most proteins that govern the integrity of the cell, the extracellular matrix, tissues, and the organism as a whole are processed through the ER, and the role of the ER tends to be particularly vital in immune cells because they produce a very large amount of protein. Thus, it is not surprising that induction of ER stress is communicated between the stressed cells and other cells in that tissue or in the organism as a whole, including immune cells. Communication governed by ER stress generally leads to inflammation that aims to control tissue damage and aid in tissue repair. However, under certain conditions, ER stress-induced inflammation exacerbates conditions such as diabetes, obesity, atherosclerosis, and cancer. In inflammatory diseases, ER stress can govern the longevity, intensity, and type of immune response, but whether the final result of ER stress-induced inflammation is detrimental or protective hinges on several factors. In this review, we discuss in detail the signaling Review Glossary Acute-phase response (APR): group of physiological processes occurring soon after the onset of infection, trauma, inflammation, and some malignant conditions. These processes include an increase in serum acute phase proteins (APPs) and vascular permeability, and development of fever, metabolic, neurological, and pathological changes. Alarmins: endogenous 'danger signals' that mediate immunomodulatory processes after their release from cells undergoing cell death or after their secretion by (non-dying) immune cells. Alarmins help in the recruitment of immune cells and re-establishment of tissue homeostasis. Autocrine signaling: signaling in which a cell secretes a biomolecule/factor that binds to the receptors/targets on the same cell and leads to biological changes in that cell. Cell autonomous: any process that can be initiated in its entirety by one particular cell, on its own, in response to stress/damage/stimulation. Chemokine: secreted chemotactic cytokines that can induce directed chemotaxis in the responsive cells. Colitis: inflammation of the colon. In a broad sense, it denotes inflammation in the large intestine: colon, caecum, and rectum. Cytokine: secreted, small, protein molecules that function predominantly in immunological intercellular communication. These include interleukins (ILs) and interferons (IFNs).

Journal of Applied Physiology, 2002

Acute stressor exposure can facilitate innate immunity and suppress acquired immunity. The present study further characterized the potentiating effect of stress on innate immunity, interleukin-1␤ (IL-1␤), and demonstrated that stress-induced potentiation of innate immunity may contribute to the stress-induced suppression of acquired immunity. The long-term effect of stress on IL-1␤ was measured by using an ex vivo approach. Sprague-Dawley rats were challenged with lipopolysaccharide (LPS) in vivo, and the IL-1␤ response was measured in vitro. Splenocytes, mesenteric lymphocytes, and peritoneal cavity cells had a dose-and time-dependent ex vivo IL-1␤ response to LPS. Rats that were exposed to inescapable shock (IS, 100 1.6 mA, 5-s tail shocks, 60-s intertrial interval) and challenged with a submaximal dose of LPS 4 days later had elevated IL-1␤ measured ex vivo. To test whether the acute stress-induced elevation in IL-1␤ contributes to the long-term suppression in acquired immunity, IL-1␤ receptors were blocked for 24 h after stress. Serum anti-keyhole limpet hemocyanin (KLH) immunoglobulin (Ig) was measured. In addition, the acute elevation (2 h post-IS) of splenic IL-1␤ in the absence of antigen was verified. Interleukin-1 receptor antagonist prevented IS-induced suppression in anti-KLH Ig. These data support the hypothesis that stress-induced increases in innate immunity (i.e., IL-1␤) may contribute to stress-induced suppression in acquired immunity (i.e., anti-KLH Ig). interleukin-1␤; interleukin-1 receptor antagonist; keyhole limpet hemocyanin; lipopolysaccharide ACUTE STRESSOR EXPOSURE MODULATES both innate and acquired immune function. It has been recently reported that stressor exposure can increase many measures of innate immunity. For example, the rate of benign (10, 17a) and infectious bacterial inflammation resolution (5), fever (17), macrophage/neutrophil nitric oxide (NO; Refs. 5, proinflammatory cytokines (29,, and complement activity (7, 17a) are all elevated after

Psychoneuroendocrinology, 2012

This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.

The psychoneuroimmunology of chronic disease: Exploring the links between inflammation, stress, and illness.

Stress occurs when environmental demands exceed the individual's adaptive capacity or ability to cope (Cohen, Kessler, & Gordon, 1995). These environmental demands are termed stressors and include negative life events such as family conflict, job strain, unemployment, abuse, trauma, and bereavement, as well as physical stressors. To study the process of stress, researchers measure the occurrence of the environmental stressor, behavioral and biological responses to this event, and its long-term consequences. Stressors appear to have bidirectional effects on the immune system depending on whether they are acute or chronic (Dhabhar & McEwen, 1999; Segerstrom & Miller, 2004). Recent research indicates that acute stressors tend to activate aspects of innate immunity by increasing trafficking of immune cells to the site of challenge and by inducing long-lasting increases in

Brain, behavior, and immunity, 1997

Delayed type hypersensitivity (DTH) reactions are antigen-specific, cell-mediated immune responses which, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, fungi, and certain tumors) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. We have shown that acute stress administered immediately before antigenic challenge results in a significant enhancement of a skin DTH response in rats. A stress-induced trafficking or redeployment of leukocytes to the skin may be one of the factors mediating this immunoenhancement. Here we investigate the effects of varying the duration, intensity, and chronicity of stress on the DTH response and on changes in blood leukocyte distribution and glucocorticoid levels. Acute stress administered for 2 h prior to antigenic challenge, significantly enhanced the DTH response. Increasing the duration of stress from 2 h to 5 h produced the same magnitude enhancement in cutaneous DTH. Moreover, increasing the intensity of acute stress produced a significantly larger enhancement of the DTH response which was accompanied by increasing magnitudes of leukocyte redeployment. In contrast, chronic stress suppressed the DTH response when it was administered for 3 weeks before sensitization and either discontinued upon sensitization, or continued an additional week until challenge, or extended for one week after challenge. The stress-induced redeployment of peripheral blood lymphocytes was attenuated with increasing exposure to chronic stress and correlated with attenuated glucocorticoid responsivity. These results suggest that stress-induced alterations in lymphocyte redeployment may play an important role in mediating the bi-directional effects of acute versus chronic stress on cell-mediated immunity in vivo. ᭧ 1997 Academic Press

Cell Reports, 2021

Highlights d iT cells are unusually refractory to stress-and glucocorticoidinduced apoptosis d Chronic stress curbs both T H 1-and T H 2-type responses orchestrated by iT cells d Stress incapacitates iNKT cells via intrinsic glucocorticoid receptor signaling d Stress-elicited glucocorticoids impair the antitumor activity of iNKT cells

Clinical Therapeutics, 2020

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Frontiers in immunology, 2017

Infectious and sterile inflammation is induced by activation of innate immune cells. Triggering of toll-like receptors by pathogen-associated molecular pattern or damage-associated molecular pattern (PAMP or DAMP) molecules generates reactive oxygen species that in turn induce production and activation of pro-inflammatory cytokines such as IL-1β. Recent evidence indicates that cell stress due to common events, like starvation, enhanced metabolic demand, cold or heat, not only potentiates inflammation but may also directly trigger it in the absence of PAMPs or DAMPs. Stress-mediated inflammation is also a common feature of many hereditary disorders, due to the proteotoxic effects of mutant proteins. We propose that harmful mutant proteins can induce dysregulated IL-1β production and inflammation through different pathways depending on the cell type involved. When expressed in professional inflammatory cells, stress induced by the mutant protein activates in a cell-autonomous way the ...

Physiology & Behavior, 2002

Exposure to acute stress modulates immune function. Most research regarding stress and immunity has described the deleterious effects of stress. Recent studies, however, indicate that acute stress enhances many features of innate immunity. For example, exposure to acute stress reduced the time required to resolve inflammation produced by subcutaneous injection of streptomycin-killed, benign bacteria. It is unclear if this change in inflammation would be advantageous to the organism if challenged with living, infectious bacteria. Thus, the current experiments examined the effect of acute stressor exposure on inflammation development and resolution after a naturalistic, live bacterial challenge. In addition, nitric oxide (NO), an important bactericidal mediator, was measured at the inflammatory site. Rats (F344) were exposed to acute stress (100, 5-s, 1.6 mA tailshocks) and subcutaneously injected with live Escherichia coli ($ 2.5 Â 10 9 colony forming units [CFU]). Stressed rats attained their peak inflammatory size quicker, resolved their inflammation 10-14 days faster, experienced less bacterial-induced weight loss and released 300% greater NO at the inflammatory site than nonstressed controls. Thus, acute stress improved recovery from bacterially induced inflammation possibly due to local elevations in NO.

The EMBO Journal, 2013

The innate immune cell network detects specific microbes and damages to cell integrity in order to coordinate and polarize the immune response against invading pathogens. In recent years, a cross-talk between microbialsensing pathways and endoplasmic reticulum (ER) homeostasis has been discovered and have attracted the attention of many researchers from the inflammation field. Abnormal accumulation of proteins in the ER can be seen as a sign of cellular malfunction and triggers a collection of conserved emergency rescue pathways. These signalling cascades, which increase ER homeostasis and favour cell survival, are collectively known as the unfolded protein response (UPR). The induction or activation by microbial stimuli of several molecules linked to the ER stress response pathway have led to the conclusion that microbe sensing by immunocytes is generally associated with an UPR, which serves as a signal amplification cascade favouring inflammatory cytokines production. Induction of the UPR alone was shown to promote inflammation in different cellular and pathological models. Here we discuss how the innate immune and ER-signalling pathways intersect. Moreover, we propose that the induction of UPR-related molecules by microbial products does not necessarily reflect ER stress, but instead is an integral part of a specific transcription programme controlled by innate immunity receptors.