Christian Woiciechowsky

Mechanisms of brain-mediated systemic anti-inflammatory syndrome causing immunodepression.

Overwhelming inflammatory immune response can result in systemic inflammation and septic shock. To prevent excessive and deleterious action of proinflammatory cytokines after they have produced their initial beneficial effects, the immune system can release several anti-inflammatory mediators, including interleukin-10, interleukin-1 receptor antagonist, and soluble tumor necrosis factor receptors, thus initiating a compensatory anti-inflammatory response syndrome. However, in vivo the delicate balance between pro- and anti-inflammatory responses is additionally controlled by the central nervous system. Therefore, proinflammatory cytokines stimulate the hypothalamic-pituitary-adrenal axis and enhance sympathetic nerve system activity. The mediators of these neuroimmune pathways can again suppress immune cell functions to control systemic inflammation. The question is, however, what happens if the immunoinhibitory CNS pathways are activated without systemic inflammation? This can result from production of cytokines in the brain following infection, injury, or ischemia or in response to various stressors (e.g., life events, depression, anxiety) or directly from brainstem irritation. The answer is that this may generate a brain-mediated immunodepression. Many animal and clinical studies have demonstrated a stress and brain cytokine mediated decrease in the cellular immune response at the lymphocyte level. More recently, the importance of monocytes in systemic immunocapacity has been shown. Monocytic inactivation with decreased capability of antigen presentation and depressed secretion of proinflammatory cytokines increases the risk of infectious complications. Interestingly, cytokines in the brain and other stressors can also generate systemic immunodepression at the monocyte level. In this scenario the catecholamine-induced release of the potent anti-inflammatory cytokine interleukin-10 is a newly discovered mechanism of the brain-mediated monocyte deactivation in addition to the well known immunosuppressive action of glucocorticoids. Furthermore, other neuropeptides such as α-melanocyte-stimulating hormone and β-endorphin which can be released in stressful situations have also inhibitory effects on immune cells. Thus mediators of the CNS are implicated in the regulation of immune functions and may play a role in both conditioning the hosts response to endogenous or exogenous stimuli and generating a brain-mediated immunodepression.

Brain-IL-1β induces local inflammation but systemic anti-inflammatory response through stimulation of both hypothalamic–pituitary–adrenal axis and sympathetic nervous system

Abstract It is well established that systemic inflammation induces a counter-regulatory anti-inflammatory response particularly resulting in deactivation of monocytes/macrophages. However, recently we demonstrated a systemic anti-inflammatory response without preceding signs of systemic inflammation in patients with brain injury/surgery and release of cytokines into the cerebrospinal fluid (CSF). In order to analyze the mechanisms and pathways of systemic immunodepression resulting from sterile cerebral inflammation we established an animal model using continuous intra-cerebroventricular (i.c.v.) or intra-hypothalamic (i.h.) infusion of rat recombinant (rr) tumor necrosis factor (TNF)-α and interleukin (IL)-1β for 48 h. Controls received intra-venous (i.v.) cytokine administration. Interestingly, i.c.v. and i.h. infusion of IL-1β but not TNF-α produced distinct signs of central nervous system (CNS) inflammation. Correspondingly, i.c.v. infusion of IL-1β particularly diminished the TNF-α but increased the IL-10 concentration in whole blood cultures after endotoxin stimulation. All parameters normalized within 48 h after termination of the infusion. Blocking the hypothalamic–pituitary–adrenal (HPA) axis by hypophysectomy (HPX) led to complete recovery of the diminished TNF-α concentration and temporarily inhibited the IL-10 increase. Blocking the sympathetic nervous system (SNS) transmission by application of the β 2 -adrenoreceptor antagonist propranolol not only inhibited the increase but further downregulated the endotoxin induced IL-10 concentration in the media of whole blood cell cultures, whereas the TNF-α decrease was only partially prevented. Interestingly, HPX and propranolol also diminished the cell invasion into the CSF. In summary, activation of both the HPA axis and the SNS plays an important role in systemic anti-inflammatory response resulting from cytokines in brain and cerebral inflammation.

Transcallosal removal of lesions affecting the third ventricle: an anatomic and clinical study.

A series of 54 patients with lesions affecting the third ventricle with a wide range of pathology were operated on by the transcallosal approach. Hydrocephalus was present in 68.5% of all patients, and preoperative shunting was performed in 73.0% of them. Before the partial callosotomy, 16 patients were studied by the use of a cognitive, affective, and behavioral battery, which was repeated 10 and 100 days after the operation. No physiological consequences were ever observed after the partial commissurotomy. The postoperative callosal defect was verified by magnetic resonance imaging. Furthermore, 40 formalin-fixed brains were sectioned to study the variations of the anterior cerebral arteries. On the other hand, magnetic resonance imaging measurements of the corpus callosum in 40 normal subjects were performed to establish a classification system for the corpus callosal area. The results showed a wide variability of the cross-sectional area of the corpus callosum. The differences in the thickness of the truncus were responsible for this variability; the length of the corpus callosum was uniform. This may suggest that subjects with a large corpus callosum may have more interhemispheric connections with higher specialization of each hemisphere and that a smaller number of callosal connections may correlate with more ipsilateral pathways and more independent hemispheres. The results and the clinical as well as anatomical material indicate that the anterior transcallosal route is a safe and feasible alternative in the management of a wide spectrum of pathological lesions within the third ventricle and deserves preference over the transcortical technique.

Callosal and corticospinal tract function in patients with hydrocephalus: a morphometric and transcranial magnetic stimulation study

Abstract In 15 patients with symptomatic hydrocephalus, pressure-induced morphological changes of the brain and the function of callosal and corticospinal fibres were studied. Morphometry of the corpus callosum (CC) was performed on midsagittal MR images. Focal transcranial magnetic stimulation of the motor cortex was used to assess simultaneously excitatory motor responses in contralateral hand muscle (corticospinally mediated effect) and inhibition of tonic EMG activity in ipsilateral hand muscles (transcallosal inhibition (TI) of the contralateral motor cortex). Before a shunt operation, the midsagittal area of the CC was reduced by 34% on average. The height and, to a lesser degree the length, of the CC were increased before the shunt operation. Thresholds and central motor latencies of corticospinally mediated responses were normal, response amplitudes were smaller than in normal subjects. Motor thresholds increased from 38, SD 5 to 52, SD 8% (P<0.01) within 7 days after ventricular drainage, reflecting the increase in the distance between stimulation coil and brain. The threshold increase paralleled a restoration of normal anatomical conditions within 7 days after shunt operation and the improvement of motor symptoms and might be a predictor of successful decompression. Transcallosal inhibition could be elicited in all patients. The measurements of TI lay within the normal range except the duration, which was prolonged in 73% of 15 patients before shunt operation as a probable indicator of an increased dispersion of callosal conduction. The normalization of the area and shape of the CC after shunt operation and the normal corticospinal and callosal conduction times exclude degeneration, demyelination or functional block of a large proportion of callosal or corticospinal tract fibres or a substantial loss of nerve cells in motor cortex.

Brain IL-1β Increases Neutrophil and Decreases Lymphocyte Counts through Stimulation of Neuroimmune Pathways

Leukocytosis after cerebral injury is well described and may participate in the generation of cerebral damage. However, the mechanisms of brain-induced leukocytosis are still speculative. Since it is known that proinflammatory cytokines are involved in neuroimmunomodulation and since others and we have demonstrated high cytokine levels in the cerebrospinal fluid following injury, we supposed that brain cytokines may also influence leukocyte counts. In order to evaluate this hypothesis, we established an animal model using continuous intracerebroventricular (i.c.v.), intrahypothalamic (i.h.), or intravenous infusion of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and IL-1beta. Controls received vehicle solution. With this experimental paradigm we could show that i.c.v. and i.h. infusion of IL-1beta but not TNF-alpha dramatically increased neutrophil counts, whereas lymphocytes dropped. Blocking the hypothalamic-pituitary-adrenal (HPA) axis by hypophysectomy abolished the neutrophilia, whereas the lymphopenia remained unchanged. Furthermore, application of the beta2-adrenoreceptor antagonist propranolol prevented the decrease of lymphocytes and diminished the neutrophilia. All parameters normalized within 48 h after termination of infusion. So, our results demonstrate that brain IL-1beta can modify blood leukocyte counts through stimulation of both the sympathetic nervous system (SNS) and the HPA axis.

Differences in immune cell invasion into the cerebrospinal fluid and brain parenchyma during cerebral infusion of interleukin-1β

Abstract. Cytokine-mediated inflammatory cell recruitment into the brain is a critical step in the response to diverse insults, including infection, trauma, and stroke. Hence, continous intra-cerebroventricular infusion of interleukin (IL)-1β leads to an impressive cell invasion into the cerebrospinal fluid, as well as the brain parenchyma. Neither tumor necrosis factor-α nor IL-6 induced any significant cell invasion at all. However, the diverse immune cells (granulocytes, monocytes/macrophages) showed a different time course of invasion. Moreover, there was an association between the number of infiltrating immune cells and the infused IL-1 concentration. By analyzing intra-brain immune events, we demonstrated a time- and dose-dependent induction of intercellular adhesion molecule (ICAM)-1, whereas there were no differences for P-selectin, vascular cell adhesion molecule (VCAM)-1, and monocyte-chemotractant protein (MCP)-1, comparing vehicle and IL-1-infused animals. In conclusion, we assume IL-1β to be a key cytokine for the granulocyte and monocyte recruitment into the central nervous system after various insults. However, granulocytes anticipate monocyte invasion.

Catecholamine-induced interleukin-10 release: a key mechanism in systemic immunodepression after brain injury

BackgroundInfections after severe brain injury or polytrauma are still a problem, and may be the result of a brain-mediated disturbed systemic immunoreactivity. The mechanism that connects initial brain affection and systemic immunodepression, however, is still poorly understood.ReviewIn order to analyze the influence of the sympathetic nervous system in the context of brain injury on systemic immune functions, we performed various in vitro, in vivo and clinical studies. We were able to demonstrate that catecholamines trigger the release of the strong anti-inflammatory cytokine interleukin (IL)-10 from peripheral blood mononuclear cells and monocytes. In animal models we were able to show that increased intracranial pressure as well as intracerebral proinflammatory cytokines (eg IL-1β) produce a rapid systemic IL-10 release through sympathetic activation. Thus, in both models, the predominant role of catecholamines for this effect was confirmed by the complete prevention of IL-10 increase after β-adrenoreceptor blockade. Moreover, in clinical studies we clearly demonstrated that neurosurgical procedures involving brain-stem manipulation invoke sympathetic activation and a rapid systemic IL-10 release. Remarkably, this was associated with monocytic deactivation – a sign of systemic immunodepression and a high risk of infectious complications.Finally, these data were validated in patients with accidental brain injury, in whom we demonstrated a correlation between the severity of injury, sympathetic activation, IL-10 plasma levels and the incidence of infectious complications.ConclusionIn summary, we suppose that activation of inhibitory neuroimmune pathways like the sympathetic nervous system, but also the hypothalamic-pituitary-adrenal axis, may trigger a systemic anti-inflammatory response syndrome that leads to systemic immunodepression. In this process the catecholamine-mediated systemic IL-10 release that causes monocytic deactivation may be a key mechanism.

Oligodeoxynucleotides induce brain inflammation in rats when infused intracerebroventricularly

Antisense oligodeoxynucleotides (ODNs) can inhibit gene expression in a specific manner. However, several studies described problems with cerebral ODN application. Here, we investigated the immune effects (interleukin-6 (IL-6) release, cell invasion into cerebrospinal fluid (CSF) and brain parenchyma) of non-sense randomized ODNs with different counterions (NH(4)(+), Na(+)) and modifications (with or without thioat-backbone) which were administered intracerebroventricularly for 48 h using osmotic mini-pumps in a rat model. All animals receiving ODNs showed increased IL-6 levels in the CSF as well as cell invasion into the CSF and brain parenchyma (P<0.05). However, the use of thioat-backbone and ammonium as the counterion induced the highest IL-6 levels (7210+/-1696 pg/ml, P<0.05) and the highest cell numbers in the CSF (31.6+/-15.5x10(5)/ml, P<0.05) as well as brain parenchyma (268.1+/-143.2 HIS-48+ cells/mm(2), P<0.01; and 31.3+/-10.7 OX-6+cells/mm(2), P<0.05) compared with the other groups.

Immune Monitoring and Strategies for Immune Modulation

Antimicrobial defense against pathogens plays a key role in the protection of the body’s integrity. The first level of defense is based on relatively static physical and biological natural barriers e.g. mucosa, skin, pH, natural intestinal and vaginal flora. If the pathogens or their toxins penetrate these barriers, the inducible acute inflammatory system consisting of humoral factors (e.g. complement, type I interferons, defensins, proteolytic enzymes, cytokines) and inflammatory cells (e.g. mast cells, macrophages) located at body surfaces (skin, intestine, respiratory tract) react within minutes to hours. The resulting acute local inflammation exhibits strong antimicrobial properties. This response is also important for tissue regeneration and wound healing explaining the observation that inflammation is activated following sterile tissue injury (trauma, hypoxia). In addition, local inflammation activates the endothelium amplifying and attracting further humoral and cellular components (e.g. platelets, granulocytes, NK cells). Endothelial cells play an important role in induction of this secondary phase of acute inflammation. Normally, they form a barrier between the components of the blood circulation and tissue that can be passed by gases and low molecular weight substances only. Resting endothelial cells express anti-coagulant molecules like thrombomodulin at their surface to prevent coagulation.

Influence of brain-derived cytokines on the immune response

The original notion that the brain represents an “immune-privileged” organ lacking the capability to produce an inflammatory response to an injury would appear, at least as such a simple statement, no longer tenable. Indeed, accumulating evidence has shown that the brain can mount a well-defined inflammatory response to a variety of insults including trauma, ischemia, transplantation, viral infections, toxins as well as neurodegenerative processes. Many aspects of this centrally-derived inflammatory response parallel, to some extent, the nature of such a reaction in the periphery. The main sources of brain-cytokines are endothelial cells, invading immune cells, astrocytes and microglia. These cells can produce cytokines such as interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-α in response to hypoxia, endotoxin and cell detritus [1, 2, 3, 4, 5, 6]. Moreover, marked increases of TNF-α were localized immunocytochemically to neurons of injured cerebral cortex. Knoblach et al. (1999) reported that intracerebroventricular administration of a selective TNF-a antagonist at 15 minutes before and one hour after traumatic brain injury (TBI), improved performance in a series of standardized motor tasks after injury. In contrast, intravenous administration of soluble TNF-α receptor fusion protein (sTNFR:Fc) (0.2, 1 or 5 mg/kg) at 15 minutes after trauma did not improve motor outcome. Collectively, this evidence suggests that enhanced early neuronal expression of TNF-α after TBI contributes to subsequent neurological dysfunction [7]. Woodrofe et al. (1991) demonstrated increased levels of IL-1 and IL-6 in the rat brain parenchyma following mechanical injury by microdialysis [1].