Ning Quan

Brain-immune communication pathways.

Communication between the central nervous and immune systems lies at the heart of the neuroimmune axis. We trace here some of the major conceptual hurdles which were raised, first against the acceptance of a neuroimmune axis and later in understanding it. We review the major concepts formulated and established during the last two decades and focus on four pathways that have been proposed as important in communication: the neural route, circumventricular organs, blood-brain barrier transport of cytokines, and secretions from BBB cells. These and other pathways have established the existence of a neuroimmune axis, but raise new questions on how they act and interact with one another.

Social stress increases the susceptibility to endotoxic shock

The influence of social disruption stress (SDR) on the susceptibility to endotoxic shock was investigated. SDR was found to increase the mortality of mice when they were challenged with the bacterial endotoxin lipopolysaccharide (LPS). Histological examination of SDR animals after LPS injection revealed widespread disseminated intravascular coagulation in the brain and lung, extensive meningitis in the brain, severe hemorrhage in the lung, necrosis in the liver, and lymphoid hyperplasia in the spleen, indicating inflammatory organ damage. In situ hybridization histochemical analysis showed that the expression of the glucocorticoid receptor mRNA was down-regulated in the brain and spleen of SDR animals while the ratio of expression of AVP/CRH-the two adrenocorticotropic hormone secretagogue, increased. After LPS injection, the expression of pro-inflammatory cytokines, IL-1beta and TNF-alpha, was found significantly higher in the lung, liver, spleen, and brain of the SDR mice as compared with the LPS-injected home cage control animals. Taken together, these results show that SDR stress increases the susceptibility to endotoxic shock and suggest that the development of glucocorticoid resistance and increased production of pro-inflammatory cytokines are the mechanisms for this behavior-induced susceptibility to endotoxic shock.

Short day lengths attenuate the symptoms of infection in Siberian hamsters

Symptoms of infection, such as fever, anorexia and lethargy, are ubiquitous among vertebrates. Rather than nonspecific manifestations of illness, these responses are organized, adaptive strategies that are often critical to host survival. During times of energetic shortage such as winter, however, it may be detrimental for individuals to prolong energetically demanding symptoms such as fever. Individuals may adjust their immune responses prior to winter by using day length to anticipate energetically–demanding conditions. If the expression of sickness behaviours is constrained by energy availability, then cytokine production, fever, and anorexia should be attenuated in infected Siberian hamsters housed under simulated winter photoperiods. We housed hamsters in either long (14 L : 10 D) or short (10 L : 14 D) day lengths and assessed cytokines, anorexia and fever following injections of lipopolysaccharide (LPS). Short days attenuated the response to lipopolysaccharide, by decreasing the production of interleukin (IL)–6 and IL–1β, and diminishing the duration of fever and anorexia. Short–day exposure in hamsters also decreased the ingestion of dietary iron, a nutrient vital to bacterial replication. Taken together, short day lengths attenuated the symptoms of infection, presumably to optimize energy expenditure and survival outcome.

Endothelial-Specific Knockdown of Interleukin-1 (IL-1) Type 1 Receptor Differentially Alters CNS Responses to IL-1 Depending on Its Route of Administration

Interleukin-1 (IL-1) has been implicated as a critical mediator of neuroimmune communication. In the brain, the functional receptor for IL-1, type 1 IL-1 receptor (IL-1R1), is localized primarily to the endothelial cells. In this study, we created an endothelial-specific IL-1R1 knockdown model to test the role of endothelial IL-1R1 in mediating the effects of IL-1. Neuronal activation in the hypothalamus was measured by c-fos expression in the paraventricular nucleus and the ventromedial preoptic area. In addition, two specific sickness symptoms, febrile response and reduction of locomotor activity, were studied. Intracerebroventricular injection of IL-1 induced leukocyte infiltration into the CNS, activation of hypothalamic neurons, fever, and reduced locomotor activity in normal mice. Endothelial-specific knockdown of IL-1R1 abrogated all these responses. Intraperitoneal injection of IL-1 also induced neuronal activation in the hypothalamus, fever, and reduced locomotor activity, without inducing leukocyte infiltration into the brain. Endothelial-specific knockdown of IL-1R1 suppressed intraperitoneal IL-1-induced fever, but not the induction of c-fos in hypothalamus. When IL-1 was given intravenously, endothelial knockdown of IL-1R1 abolished intravenous IL-1-induced CNS activation and the two monitored sickness symptoms. In addition, endothelial-specific knockdown of IL-1R1 blocked the induction of cyclooxygenase-2 expression induced by all three routes of IL-1 administration. These results show that the effects of intravenous and intracerebroventricular IL-1 are mediated by endothelial IL-1R1, whereas the effects of intraperitoneal IL-1 are partially dependent on endothelial IL-1R1.

Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice.

Splenocytes from socially stressed male mice display functional glucocorticoid (GC) resistance, viz., the antiproliferative effects of GC on lipopolysaccharide (LPS)-stimulated splenocytes is absent. In this study, we investigated changes in the structure and function of the glucocorticoid receptor (GR) in socially stressed animals. Changes of GR at both DNA and RNA levels were excluded. Reduced GR function was restricted to macrophages (CD11b(+)) in association with impaired nuclear translocation of GR after GC stimulation. Consequently, GC failed to block the activation of NF-kappa B in these cells. Thus, impaired nuclear translocation of GR and the lack of transcriptional suppression of NF-kappa B by GC were identified as the molecular mechanisms responsible for the observed GC resistance in spleens of socially stressed mice.

Knockdown of Interleukin-1 Receptor Type-1 on Endothelial Cells Attenuated Stress-Induced Neuroinflammation and Prevented Anxiety-Like Behavior

Interleukin-1β (IL-1β) is an inflammatory cytokine that plays a prominent role in stress-induced behavioral changes. In a model of repeated social defeat (RSD), elevated IL-1β expression in the brain was associated with recruitment of primed macrophages that were necessary for development of anxiety-like behavior. Moreover, microglia activation and anxiety-like behavior associated with RSD did not occur in IL-1 receptor type-1 knock-out (IL-1R1KO) mice. Therefore, the objective of this study was to examine the role of IL-1 signaling in RSD-induced macrophage trafficking to the brain and anxiety-like behavior. Initial studies revealed that RSD did not increase circulating myeloid cells in IL-1R1KO mice, resulting in limited macrophage trafficking to the brain. In addition, IL-1R1KO bone marrow-chimera mice showed that IL-1R1 expression was essential for macrophage trafficking into the brain. To differentiate cellular mediators of stress-induced IL-1 signaling, endothelial-specific IL-1R1 knock-down (eIL-1R1kd) mice were used. Both wild-type (WT) and eIL-1R1kd mice had increased circulating monocytes, recruitment of macrophages to the brain, and altered microglia activation after RSD. Nonetheless, RSD-induced expression of IL-1β, TNF-α, and IL-6 mRNA in brain CD11b+ cells was attenuated in eIL-1R1kd mice compared with WT. Moreover, anxiety-like behavior did not develop in eIL-1R1kd mice. Collectively, these findings demonstrated that there was limited RSD-induced priming of myeloid cells in IL-1R1KO mice and disrupted propagation of neuroinflammatory signals in the brain of eIL-1R1kd mice. Furthermore, these data showed that transduction of IL-1 signaling by endothelial cells potentiates stress-induced neuroinflammation and promotes anxiety-like behavior.

Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen

Frequent or chronic stress as a result of repeated or persistent exposure to social challenges has been shown to affect the glucocorticoid (GC) responsiveness of immune cells in mice. Lipopolysaccharide-stimulated splenocytes of mice that were repeatedly subjected to social disruption were less sensitive to the anti-inflammatory actions of GC as evident from an increased production of pro-inflammatory cytokines and enhanced cell survival. The development of functional GC resistance was accompanied by the accumulation of GC-insensitive CD11b(+) cells in the spleen. These cells were shown to exhibit impaired nuclear translocation of the GC receptor and lack of GC-induced suppression of NF-kappaB. Similar impairments in GC receptor function have been reported after in vitro treatment of various cell lines with interleukin (IL)-1. The aim of this study was to elucidate whether IL-1 is a critical factor for the development of GC resistance in socially stressed mice. In the first experiment, we investigated if repeated social stress alters plasma levels and tissue gene expression of IL-1alpha and IL-1beta. It revealed that recurrent stressor exposure significantly increased splenic and hepatic mRNA expression and the plasma protein level of IL-1beta, and hepatic mRNA expression of IL-1alpha. In the second experiment, IL-1 receptor type 1 (IL1R1)-deficient mice were subjected to the stressor and both the tissue distribution of CD11b(+) cells and the GC sensitivity of the splenocytes were compared to wildtype mice. Mice lacking the IL1R1 exhibited adrenal hypertrophy, thymic involution, and elevated serum corticosterone levels in response to the stressor but did not show splenic accumulation of CD11b(+) cells and failed to develop GC resistance. These findings suggest that IL-1 plays a critical role in the development of the social stress-associated GC resistance in the murine spleen.

Endothelial activation is an intermediate step for peripheral lipopolysaccharide induced activation of paraventricular nucleus

Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) activates the paraventricular nuclei of the hypothalamus (PVN), and consequently the hypothalamus-pituitary adrenal axis. Inflammatory cytokine interleukin-1 (IL-1) has been considered as a key mediator that translates the peripheral LPS stimulation into neuronal activation in the PVN. Several studies attempting to localize the expression of receptors for IL-1 (IL-1R), however, have failed to detect IL-1R on PVN neurons. It remains unclear, therefore, how IL-1 might stimulate the neurons of the PVN. In this study, we traced the cellular responsiveness to IL-1 by measuring the mRNA production of the cytokine responsive gene IkappaBalpha in the PVN. After either peripheral injection LPS or intracerebroventricular (i.c.v.) injection of IL-1beta, IkappaBalpha mRNA was found mostly in endothelial cells of the brain with the highest level of expression in PVN blood vessels. In addition, both injections also induced the expression of cyclooxygenase-2 in brain endothelial cells. Pretreatment with indomethacin, a cyclooxygenase inhibitor, blocked LPS and IL-1 induced neuronal activation in the PVN, but did not reduce the induction of IkappaBalpha in PVN endothelium. These results show that IL-1 acting on the endothelial cells of the brain, particularly in the PVN, may be an intermediate step relating peripheral immune signals to the brain.

Restraint stress alters the expression of interleukin-1 and keratinocyte growth factor at the wound site: an in situ hybridization study

Stress has a negative impact on wound healing. This murine study evaluated the effect of restraint stress (RST) on interleukin-1 (IL-1) and keratinocyte growth factor-1 (KGF-1) gene expression in cutaneous wounds by in situ hybridization. At day 1, RST mice had reduced frequency of IL-1beta mRNA-expressing fibroblasts compared to control mice. At day 3, RST mice had reduced frequencies of IL-1beta mRNA-expressing leukocytes, KGF-1 mRNA-expressing fibroblasts, and thin proliferating zones of epithelium. At day 5, RST mice had persistent leukocytic foci and reduced granulation tissue. Therefore, stress-induced alterations in cutaneous proinflammatory cytokine and growth factor expression are associated with significant histological changes in healing wounds.

Neuroinflammation: The Devil is in the Details

There is significant interest in understanding inflammatory responses within the brain and spinal cord. Inflammatory responses that are centralized within the brain and spinal cord are generally referred to as ‘neuroinflammatory’. Aspects of neuroinflammation vary within the context of disease, injury, infection, or stress. The context, course, and duration of these inflammatory responses are all critical aspects in the understanding of these processes and their corresponding physiological, biochemical, and behavioral consequences. Microglia, innate immune cells of the CNS, play key roles in mediating these neuroinflammatory responses. Because the connotation of neuroinflammation is inherently negative and maladaptive, the majority of research focus is on the pathological aspects of neuroinflammation. There are, however, several degrees of neuroinflammatory responses, some of which are positive. In many circumstances including CNS injury, there is a balance of inflammatory and intrinsic repair processes that influences functional recovery. In addition, there are several other examples where communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. The purpose of this review is to distinguish different variations of neuroinflammation in a context‐specific manner and detail both positive and negative aspects of neuroinflammatory processes.