Inflammation and Immunity in Depression

Basic Science and Clinical Applications

Bernhard Baune

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128110744
• Topic: Medicine
• Subtopic: Psychiatry & Mental Health

Inflammation and Immunity in Depression: Basic Science and Clinical Applications is the first book to move beyond the established theory of cytokine-induced depression and explore the broader role the immune system plays in this devastating mood disorder. The book fully explores the most recent lines of research into this rapidly advancing field, including alterations of T-cells, the neurobiological implications of neuroinflammation and immune alterations for brain development and function, and the genetic components of neuroinflammation in depression, including the relationships between stress and inflammation that are revealing gene-environment interactions in the disorder.

Combining contributions from researchers worldwide, this book provides the most comprehensive discussion available today on the involvement of the innate immune and adaptive immune systems in depressive disorder. Chapters span neuroscience, psychology, clinical applications and future directions, making this book an invaluable resource for advanced students, researchers and practitioners who need to understand the complex and varied role of inflammation and immune responses in depression.

• Synthesizes current knowledge of inflammation and immunity in depression, ranging from basic neuroscience research, to clinical applications in psychiatry
• Expands on the long-established theory of cytokine-induced depression to discuss broader involvement of the immune system
• Explores translational potential of targeting immune dysfunction for clinical interventions

Chapter 1

Depression-Associated Cellular Components of the Innate and Adaptive Immune System

Diana Ahmetspahic; Dana Brinker; Judith Alferink University of Münster, Münster, Germany

Abstract

Major depressive disorder (MDD) is a serious and debilitating mood disorder that affects millions of people each year worldwide. A convergence of evidence has indicated that patients with MDD exhibit altered immune responsivity. The cytokine hypothesis of depression proposed in the 1990s is based on numerous studies showing elevated circulating proinflammatory cytokine levels and impaired cellular immunity in patients with MDD and in animal models of depression. In this section, we highlight aspects of innate and adaptive immunity that have been implicated in the pathophysiology of MDD and depression-associated behavior. We further discuss the significance of key immune cell types that lie at the interface between innate to adaptive immunity in the context of MDD. Finally, we introduce T-helper cell subsets of the adaptive immune responses, while their specific role in depression will be discussed in greater detail in a separate chapter.

Keywords

Depression; Immune response; Innate immunity; Myeloid cells; T-helper cells

The Innate Immune System

The immune system, which defends the organism against potential pathogens and carcinogenesis, involves various tissues, cell types, and soluble components. It is generally divided into two major arms: innate immunity and adaptive immunity (Medzhitov et al., 2011). The innate immune system represents the first line of defense against invading microbial pathogens. In 1989, Charles Janeway Jr. postulated a revolutionary theory to explain what he called the “immunologist's dirty little secret” (Janeway, 2013). The classical self-nonself paradigm at that time did not explain why a foreign antigen alone was insufficient to elicit an adaptive immune response, and “dirty extracts” like mycobacteria, mineral oil, or aluminum hydroxide had to be coadministered for induction of an efficient T- and B-cell response. Janeway postulated two key features of innate immunity: the capacity to discriminate between “noninfectious self from infectious nonself” and to activate the adaptive immune response. He suggested that germline-encoded receptors on innate immune cells may recognize evolutionarily conserved microbial patterns that would thus drive the adaptive response. It is meanwhile well established that within minutes of encountering pathogens, innate immune cells recognize distinct evolutionarily conserved molecular structures called pathogen-associated molecular patterns (PAMPs) (Medzhitov, 2009). In events of trauma or tissue injury, damage-associated molecular-pattern (DAMP) molecules released by dead, damaged, or stressed cells from the host itself can also trigger innate responses. DAMPs encompass a variety of molecule types, including heat-shock proteins, cytoplasmic complex proteins S100A8/S100A9, high-mobility group box 1 DNA-binding proteins in the nucleus, and ATP. These molecules bind various pattern-recognition receptors (PRRs) expressed within the cytosol or on the membranes of innate immune cells, such as toll-like receptors (TLRs), C-type lectin receptors (CLRs), leucine-rich repeat (LRR)-containing (or NOD-like) receptors (NLRs), RIG-I-like receptors (RLRs), and AIM2-like receptors (ALRs). Subsequently, activated PRRs trigger signaling cascades, resulting in the release of cytokines and other factors by myeloid cells that orchestrate the recruitment of leukocytes to inflammatory sites and local effector functions (Iwasaki & Medzhitov, 2015). Myeloid cells that stem from common progenitors, descendants of hematopoietic stem cells in the bone marrow, are a highly heterogeneous population of innate immune cells, including granulocytes (e.g., neutrophils, basophils, eosinophils, and mast cells), monocytes/macrophages, and dendritic cells (DCs) (Akashi, Traver, Miyamoto, & Weissman, 2000) (Fig. 1). Current knowledge about the immune function of specific myeloid cell subsets, namely, neutrophils and monocytes, and their involvement in MDD is summarized in the following section.

Fig. 1 Schematic overview of human hematopoiesis of myeloid and lymphoid lineages. ILC, innate lymphoid cell.

Role of Neutrophils in Innate Immunity and MDD

Neutrophils (aka neutrophil polymorphonuclear granulocytes) account for 35%–80% of circulating leukocytes in mammals and are the ultimate first line of defense against acute infection. Peripherally circulating neutrophils are short-lived, terminally differentiated cells with a half-life of 8–12 h. It is currently discussed that distinct neutrophil subsets that exert inflammatory or antiinflammatory actions may exist under physiological and disease conditions (Kolaczkowska & Kubes, 2013). However, decisive markers for these functionally diverse neutrophil subsets have not been established. Activated neutrophils utilize various cytotoxic mechanisms to restrict pathogen replication, including engulfing invading pathogens by phagocytosis, degrading them by way of releasing granule-derived antimicrobial peptides, and producing reactive oxygen species (ROS). Quite remarkably, activated neutrophils can also trap and kill pathogens by forming so-called neutrophil extracellular traps made up of extracellular weblike fibers of granule antimicrobial proteins and nuclear contents (Kolaczkowska & Kubes, 2013).

Originally, neutrophils were thought to act exclusively as effector cells in innate immunity. However, in recent years, they have been shown to also be capable of modulating macrophage and DC-dependent functions in adaptive immune responses via cell-cell interactions and soluble mediators (Mayadas, Cullere, & Lowell, 2014). Upon making contact with endothelial cells, neutrophils undergo phenotypic changes and upregulate adhesion molecules, chemokine receptors, and proteases, such as neutrophil elastase. When they populate inflammatory sites, they exhibit an extended half-life of up to 1–2 days, a greater capacity to migrate, cytotoxicity, and protease release, and they may also form neutrophil extracellular traps (Kolaczkowska & Kubes, 2013). Interestingly, neutrophils also leave sites of tissue injury and migrate back into the vasculature (de Oliveira, Rosowski, & Huttenlocher, 2016). The contribution of this “reverse migration” to resolution of inflammation has not yet been resolved.

Increased neutrophil counts and percentages have been observed in peripheral blood of patients with MDD (Darko, Rose, Gillin, Golshan, & Baird, 1988; Irwin, Smith, & Gillin, 1987; Kronfol & House, 1989; Maes, Lambrechts, Suy, Vandervorst, & Bosmans, 1994; McAdams & Leonard, 1993). A meta-analysis demonstrated a relative increase in circulating neutrophils that was paralleled by a decrease in lymphocytes in MDD patients (Zorrilla et al., 2001). Neutrophil-to-lymphocyte ratio (NLR) is an indicator of systemic inflammation whose prognostic value has been demonstrated in cancer, cardiovascular diseases, and inflammatory diseases (Isaac et al., 2016). Nonmedicated patients with MDD have been shown to express a high NLR, compared with healthy individuals, whereas medicated MDD patients (taking selective serotonin reuptake inhibitors (SSRIs)) had normalized physiological NLRs (Demircan, Gozel, Kilinc, Ulu, & Atmaca, 2016). A recent study evaluating NLRs and platelet-lymphocyte ratios (PLRs) of inpatients and outpatients with MDD did not reveal a relationship between severity of depression and NLR, but did demonstrate higher PLRs in patients suffering from MDD with psychotic features than in those suffering from other subtypes of depression (Kayhan, Gunduz, Ersoy, Kandeger, & Annagur, 2017).

Also neutrophil functions such as phagocytosis and ROS production have been investigated in MDD patients. Phagocytosis in immune cells can be assessed by in vitro uptake of fluorescently labeled microorganisms or particles coated with microbial cell-wall components (e.g., the yeast protein zymosan). In depressed individuals, phagocytosis of zymosan particles assessed with chemiluminescence was shown to be impaired in polymorphonuclear cells that include several types of granulocytes among those neutrophils. Reduced polymorphonuclear activity was normalized in response to effective therapy but not in nonresponders (O'Neill & Leonard, 1990). In a later study from the same group, phagocytosis was specifically investigated in monocytes and neutrophils from depressed patients. Neutrophil phagocytosis was reduced during acute phase of disease but returned to control values on recovery. Interestingly, monocyte phagocytosis was increased and returned to control values following remission (McAdams & Leonard, 1993). A subsequent meta-analysis also reported decreased cellular neutrophil function in MDD (Zorrilla et al., 2001). Maes et al. demonstrated that chemotaxis, superoxide release, and phagocytic capacity of circulating neutrophils were similar across diverse subtypes of depression and healthy volunteers (Maes et al., 1992). Also, no difference in neutrophil phagocytosis of Escherichia coli was detected by flow cytometry between hip fracture patients with versus without depressive symptoms (Duggal, Upton, Phillips, & Lord, 2016). Production of polymorphonuclear elastase, an index of neutrophil function, has also been assayed in MDD and found to be enhanced (Deger et al., 1996). Finally, patients with MDD, including elderly patients and patients with comorbidity in heart failure, have been reported to have increased plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), an innate antibacterial factor expressed in activated neutrophils (Naude et al., 2014). Thus, NGAL has emerged as a potential biological link between depression and cardiovascular disease. The relationship between depression and cardiovascular disease will be reviewed in a following section.

Monocytes and MDD

Monocytes are by far the most studied myeloid cell subset in relation to MDD. They are highly plastic regarding their phenotypes and population sizes. Monocytes can act as phagocytes via expression of various receptors, such as Fc, complement, and scavenger receptors (Ginhoux & Jung, 2014; Ziegler-Heitbrock, 2015). Generally, circulating monocytes represent 4%–10% of white blood cells in humans and mice. Monocyte numbers surge within minutes of stress exposure or physical exertion. This phenomenon has been explained by the existence of monocyte reservoirs in area...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Chapter 1: Depression-Associated Cellular Components of the Innate and Adaptive Immune System
• Chapter 2: Childhood Microbial Experience, Immunoregulation, Inflammation, and Adult Susceptibility to Psychosocial Stressors and Depression
• Chapter 3: Neuroendocrine Abnormalities in Major Depression: An Insight Into Glucocorticoids, Cytokines, and the Kynurenine Pathway
• Chapter 4: Neurovascular Dysfunction With BBB Hyperpermeability Related to the Pathophysiology of Major Depressive Disorder
• Chapter 5: The Impact of Inflammation on Brain Function and Behavior in Rodent Models of Affective Disorders
• Chapter 6: Neurogenesis, Inflammation, and Mental Health
• Chapter 7: The Roles of T Cells in Clinical Depression
• Chapter 8: Do Chemokines Have a Role in the Pathophysiology of Depression?
• Chapter 9: Inflammasomes Action as an Important Mechanism in Experimental and Clinical Depression
• Chapter 10: Pathways Driving Neuroprogression in Depression: The Role of Immune Activation
• Chapter 11: Gene Expression of Inflammation Markers in Depression
• Chapter 12: Neuroimmunopharmacology at the Interface of Inflammation and Pharmacology Relevant to Depression
• Chapter 13: The Gut-Brain-Microbe Interaction: Relevance in Inflammation and Depression
• Chapter 14: Childhood Trauma and Adulthood Immune Activation
• Chapter 15: Stress, Maltreatment, Inflammation, and Functional Brain Changes in Depression
• Chapter 16: Structural Neuroimaging of Maltreatment and Inflammation in Depression
• Chapter 17: Biological Embedding of Childhood Maltreatment in Adult Depression
• Chapter 18: Epigenetic Changes in the Immune Systems Following Early-Life Stress
• Chapter 19: Mechanisms Linking Depression, Immune System and Epigenetics During Aging
• Chapter 20: Role of Inflammation in Neuropsychiatric Comorbidity of Obesity: Experimental and Clinical Evidence
• Chapter 21: Inflammation and Depression in Patients With Autoimmune Disease, Diabetes, and Obesity
• Chapter 22: Does Inflammation Link Clinical Depression and Coronary Artery Disease?
• Chapter 23: Inflammation Genetics of Depression
• Chapter 24: Adolescent-Onset Depressive Disorders and Inflammation
• Chapter 25: Inflammation in Bipolar Disorder
• Chapter 26: Depression Subtypes and Inflammation: Atypical Rather Than Melancholic Depression Is Linked With Immunometabolic Dysregulations
• Chapter 27: Inflammation as a Marker of Clinical Response to Treatment: A Focus on Treatment-Resistant Depression
• Chapter 28: Clinical Trials of Anti-Inflammatory Treatments of Major Depression
• Chapter 29: Alcohol, Inflammation, and Depression: The Gut-Brain Axis
• Chapter 30: Efficacy of Anti-Inflammatory Treatment in Depression
• Chapter 31: Modulation of Inflammation by Antidepressants
• Chapter 32: The Biological Underpinnings of Mood Disorders Interact With Early Trauma, Sexual Abuse and Neuroticism: Implications for Psychiatric Classification and Treatment
• Chapter 33: Is There Still Hope for Treating Depression With Antiinflammatories?
• Chapter 34: Effects of Physical Exercise on Inflammation in Depression
• Chapter 35: Future Perspectives on Immune-Related Treatments
• Index