Andrew Miller, Emory University, Atlanta, USA
Brian Leonard, National University of Ireland, Galway, Ireland
Marion Leboyer, University Paris-East, France
Richard Bazinet, University of Toronto, Canada
Robert Dantzer, MD Anderson Cancer Center, Houston, USA
Roger McIntyre, University of Toronto, Canada
The Central Nervous System was once considered an immune-privileged site. Over the years accumulating evidence has shown that not only the brain has the ability to synthesize and release reactive molecules and pro-inflammatory mediators, but also has an ability to respond to injury with anti-inflammatory, pro-homeostatic mechanisms. Short-lived acute inflammatory responses are generally beneficial in neutralizing potential threats to the CNS. Conversely, sustained chronic neuroinflammatory response are potentially detrimental, they can trigger neuronal circuits impairments, astrocytic and microglia involvement and can result in long-lasting functional consequences. The Course is aimed at reaching a comprehensive understanding of the cellular and molecular mechanisms, experimental models, methodological approaches for a full understanding of the role of inflammation in psychiatric disorders. The course will be a venue where basic and clinical researchers from diverse disciplines will meet, interact, and bring cross-disciplinary insights on new basic findings to the translational stage. The following is a brief outline of the topics that will be focus of discussion during the Course.
Cytokines Sing the Blues: Mechanisms, Mediators and Translational Implications
Increasing data indicate that activation of the inflammatory response may contribute to a number of neuropsychiatric disorders including depression. Moreover, recent clinical trials suggest that inhibition of inflammation can reverse depressive symptoms in depressed patients with high inflammation. Evidence that inflammation plays a role in depression will be reviewed, especially in patients with treatment resistance. Special emphasis will be placed on the mechanisms by which inflammation alters behavior with a focus on the impact of cytokines on neurotransmitters and neurocircuits in the brain that regulate motivation and motor activity as well as anxiety, arousal and alarm. In addition, clinical factors relevant to depression and treatment resistance including childhood maltreatment, obesity and psychosocial stress will be explored in association with their impact on neuroendocrine regulation of inflammatory responses. Exciting new data on the role of T cells in depression and anxiety also will be discussed. Finally, all data presented will be placed in a translational context to allow both the clinician and basic scientist to appreciate the relevance of these new developments in immunology and neuroscience to the care of patients.
Neuroinflammatory pathways in depression: the evidence and the consequences
Over the past 20 years, evidence has accumulated to suggest that chronic low grade inflammation plays a significant role in the aetiology of major depression. The inflammatory hypothesis ( also called the macrophage hypothesis) of depression was first suggested by Smith in 1991 and further elucidated by a number of researchers. The hypothesis is based on the following observations:
(a) Pro-inflammatory cytokines (for example, IL-1 beta, IL-6,interferon-gamma, tumour necrosis factor) are raised in the serum of depressed patients, while anti-inflammatory cytokines, such as IL-4 and IL-10 and omega-3 fatty acids, are reduced.
(b) The proinflammatory cytokines can initiate depressive-like behaviour when released from macrophages and microglia by bacterial mitogens or when administered therapeutically for the treatment of hepatitis or some forms of leukaemia (e.g.: interferon alpha).
(c) These pro-inflammatory cytokines activate the HPA axis and thereby contribute to the hypercortisolaemia, a marker of major depression that contributes to the metabolic changes associated with the disorder.
(d) By increasing the activity of the tryptophan-kynurenine pathway, proinflammatory cytokines reduce brain serotonin synthesis and increase the synthesis of neurotoxins that contribute to the neurodegenerative changes that have been detected in the frontal cortex and many limbic regions of patients with major depression.
(e) The therapeutic response to the treatment of depression is correlated with a reduction in proinflammatory cytokines.
In addition to these inflammation associated changes, it is now apparent that oxidative and nitrosative pathways are also increased in depression and contribute to the neurodegenerative changes by damaging neuronal membranes and mitochondrial integrity. Such changes contribute to the medical disorders that are frequently associated with chronic inflammation (for example, rheumatoid arthritis, chronic fatigue syndrome, psoriasis, inflammatory bowel disease,type-2 diabetes). Thus the inflammatory hypothesis links the psychopathology of depression with the medical illnesses that are often co-morbid with the disorder.
Polyunsaturated Fatty Acids and neuroinflammation
The brain is highly enriched with the polyunsaturated fatty acids arachidonic acid and docosahexaenoic acid. Recent work identifying the plasma pools by which these fatty acids enter the brain has led to new position emission tomography methods to image and quantify their uptake into the human brain. Furthermore, it is now recognized that arachidonic acid and docosahexaenoic acid are precursors to specialized proresolving mediators. The regulation of brain inflammation by polyunsaturated fatty acids will be examined with a focus on brain modulation with dietary fatty acids and emerging bioactive fatty acids mediators.
Inflammation and Psychiatry: A Primer
Cytokines are intercellular communication molecules that activate or stimulate the proliferation of target cells. They have been first identified in the immune system but have since been characterized together with their receptors in other organs including the central nervous system. Inflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha are mainly produced by activated monocytes and T-cells. At the periphery these cytokines coordinate the cellular and molecular events that ultimately result in the mounting of an inflammatory response. They are expressed constitutively in the central nervous system and they function as modulators of neurotransmission and learning and memory. However, they are also expressed in an inducible manner in response to peripheral or local immune stimulation and they serve to coordinate the behavioral and metabolic components of the host response to infection. Alterations in the brain cytokine compartment play a pivotal role in the development and maintenance of the severe fatigue, mood disorders, and cognitive dysfunction that develop in physically ill patients. A number of psychiatric disorders including schizophrenia, bipolar disorders and major depressive disorders are also associated with alterations in levels of inflammatory cytokines in the blood and the cerebrospinal fluid. Some of the pathophysiological mechanisms that are involved in this association have been elucidated, making cytokine signaling pathways a viable target for the development of new therapies. Examples will be given in the field of major depressive disorders.
Depression, Diabetes and Dementia
Individuals with mood disorders and diabetes mellitus exhibit clinically significant deficits in neurocognitive function. The neurocognitive deficits noted in both populations are progressive and are more pronounced in individuals with greater illness complexity. Emerging molecular, neurophysiological, as well as imaging data indicate that a common neurobiological substrate subserves cognitive decline in both groups. Moreover, results from both post-mortem, clinical, and epidemiological studies indicate that individuals with mood disorders and diabetes are at increased risk for all-cause dementia, notably Alzheimer's disease. This foregoing collection of observations provides that basis for hypothesizing that a pathophysiological nexus exists wherein overlapping neurobiological abnormalities (e.g., neuroinflammation, oxidative/nitrosative stress, insulin signaling disturbances) contribute to cognitive decline in incident dementia. A derivative of these transdisciplinary observations is the opportunity to repurpose and develop novel approaches for mood disorders that are based on a disease model that posits a disturbance in cellular bioenergetics.
Immuno-inflammation and immuno-genetic background in Bipolar Disorder and in Schizophrenia
Signs of inflammation and immune dysfunctions have repeatedly been reported both in bipolar disorder and in schizophrenia. The growing interest for a neuro-inflammatory hypothesis in psychosis is reflected by recent findings showing the implication of particular genetic background, in particular, associations with genes belonging to innate and adaptive immune processes including the classical and the non classical Human Leukoctye Antigen (HLA) loci, interacting with specific environmental factors, such as winter-spring births, infections or urbanicity. Furthermore, as several lines of evidences support a pathophysiological role of Human Endogenous Retroviruses in psychotic disorders, potential links will be discussed. Indeed, we and others have been able to demonstrate that Human Endogenous Retrovirus-W (HERV-W) envelope gene (Env) can be activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. Recent and independent studies have shown an association between Human Endogenous Retroviruses type "W" family (HERV-W) with major psychotic disorder. In 2008, we reported for the first time presence of ENV protein in the serum of 50 % of schizophrenic patients associated with chronic inflammation measured by elevated C-Reactive Protein (CRP), a finding that has been more recently confirmed and extended to bipolar disorder. We also observed that toxoplasma Gondii, known to be able to induce reactivation of HERV-W is associated to an increased risk in bipolar disorder (Odds Ration(OR): 2.3) close to the one observed in schizophrenia (OR= 2.17). Altogether, independent studies on immuno-inflammation, immuno-genetics, viruses, and infectious diseases enable us to depict a new relationship between immuno-inflammation and psychotic disorder which may help the identification of patho-physiological mechanisms, biomarkers and innovative treatments.