Translational Neuroimmunology, Volume 7: Neuroinflammation

By Nima Rezaei and Niloufar Yazdanpanah

Translational NeuroImmunology: Neuroinflammation updates on bench to bedside studies on neurological disorders that have immunological etiologies. The book covers neuroimmunology and the principles of autoimmune and autoinflammatory neurological disorders, with multiple sclerosis as the main focus. The immunopathology, genetics and epigenetics, microbiome, diagnosis and treatment of multiple sclerosis will be explained in ten chapters. A chapter also examines distinct aspects of pericytes, with final discussions on the neurologic manifestations, diagnostic approaches and treatments of the various neuroimmune disorders and lessons learned from translational research on non-human primates and zebrafish.

All sections are presented in an accessible, practical format, making this volume a valuable resource for immunologists, neurologists and researchers in translational biomedical research.

• Gives an introduction on neuroimmunological diseases, from bench to bedside
• Encourages the development of immunologic approaches to analyze the interaction and specific properties of nervous tissue elements during development and disease
• Focuses on understanding and therapeutically manipulating immunological responses to injury, degeneration and autoimmunity in the central nervous system
• Proves changes in relevant immune and inflammatory reactions at the cellular and molecular level during the development of nervous system diseases

• Language: English
• Publisher: Academic Press
• Release date: Jun 16, 2023
• ISBN: 9780323900713

Book preview

Chapter 1: Introduction on neuroinflammation

Niloufar Yazdanpanaha,b,c; Nima Rezaeib,c,d,⁎    a School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

b Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

c Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

d Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

⁎ Corresponding author

Abstract

Peripheral inflammation can provoke a neuroinflammatory response. Neuroinflammation is the body’s intrinsic response against trauma, infection, degenerative processes, and any type of insult. Previously, the blood-brain barrier was considered as an impermeable barrier that completely isolates the CNS from other tissues in the body. However, peripheral proinflammatory mediators can pass the BBB, while BBB is also a specialized endothelium capable of secreting and transferring the mediators and allowing the immune cells to enter the CNS. Different cellular and molecular components contribute to neuroinflammation. Neuroinflammation is sometimes considered as a double-edge sword, as acute episodes can be neuroprotective, whereas chronic events can be detrimental, resulting in synaptic damage, neuronal death, and worsening of many diseases.

Keywords

Neuroinflammation; Immunity; Inflammation; Blood-brain barrier; Microglia; Astrocyte; Immune cells

1: Introduction

Interactions of different cell types, particularly leukocytes and endothelial cells, and activity of the signaling pathways mediate the systemic and local inflammatory responses. Pathogen-associated molecular patterns (PAMPs) activate innate immune responses, which are short-term immediate reactions [1]. To orchestrate the immune response, leukocytes located in damaged tissue trigger the infiltration of more immune cells by triggering the endothelial cells to express cellular adhesion molecules (CAMs) [2]. CAMs facilitate the binding between circulating leukocytes and signaling molecules on the endothelium, via binding to and arresting leukocytes. Then, the endothelium becomes permeable to the immune cells that are attracted to the site of injury. In addition, monocytes that enter the tissues convert to macrophages, which are potent cells in phagocytosis and release of inflammatory mediators to recruit more immune cells to the inflammation site [3]. Hence, the inflammatory response starts as a focused response, and then expands as a systemic reaction.

Peripheral inflammation can provoke a neuroinflammatory response. Neuroinflammation is the body’s intrinsic response against trauma, infection, degenerative processes, and any type of insult. The proinflammatory mediators that initiate the inflammatory process are either released locally in the central nervous system (CNS) or transferred to the CNS by passing the damaged blood-brain barrier (BBB) [4]. Formerly, BBB was considered as an impermeable barrier that completely isolates the CNS from other tissues in the body. However, peripheral proinflammatory mediators can pass the BBB. Also, BBB is a specialized endothelium that is capable of secreting and transferring the mediators and allowing the immune cells to enter the CNS [2,4]. Proinflammatory mediators ignite pathways leading to the activation of glial cells, including microglia and astrocytes, as the leading cellular contributors to neuroinflammation.

Neuroinflammation is sometimes considered as a double-edge sword, as acute episodes can be neuroprotective whereas chronic events can be detrimental, resulting in synaptic damage, neuronal death, and worsening of many diseases.

2: Cellular contributors

2.1: Endothelial cells

Recognizing the special traits of the endothelial cells in the BBB has elaborated how inflammation in peripheral tissues leads to prolonged detrimental neuroinflammation. Tumor necrosis factor (TNF) and some interleukins (ILs), such as TNF-α, IL-6, and IL-1β, are transferred to the CNS mainly via the physiologically incomplete BBB at the circumventricular organs, facilitated by the active transport system of the BBB. Some mediators affect the BBB’s integrity while crossing it, which in turn, increase the permeability of BBB and facilitate the entrance of leukocytes into the CNS [2,4]. Some other humoral factors also influence the passage of leukocytes through the BBB. For instance, chemokines CCL-19 and CCL-21 facilitate the adhesion of T cells to the endothelium of the BBB; in contrast, chemokine CXCL-12 decreases T cell infiltration [4].

2.2: Microglia

Microglia are the CNS-resident macrophages and the smallest type of neuroglia, which is a pivotal component in neuroinflammation. In prolonged neuroinflammatory condition, microglia preserve their activated phenotype and produce inflammatory mediators and neurotoxic substances, which may contribute to neurodegeneration [5]. Microglia in resting state have ramified appearance. Resting microglia contribute to synaptic pruning and neurogenesis processes and to neuroprotection. Activated microglial cells have amoeboid appearance. Different receptors of the complement system and of the innate immune system are expressed on microglia, for example, mannose and lectin, Toll-like receptors (TLRs)1–9, CD14, CD18, CD36, and CD38 [6]. Nucleotide oligomerization domain (NOD)-like receptors (NLRs) form the inflammasome complex, which is effective in microglial activation and recruitment [7].

Similar to other macrophages, microglia also have two opposite phenotypes (M1 or classic and M2 or alternative). M1 phenotype, provoked by TNF-α and interferon (IFN)-γ, is the effector phenotype that starts immune responses and may contribute to neuronal damage, when overactivated. TLRs and NLRs, receptors of the innate immune system, activate microglia via the classic pathway. Classic activation produce cells with M1 phenotype that express major histocompatibility complex type 2 (MHC-II) molecules, interact with T cells, and trigger adaptive immune system responses [8]. M2 phenotype, provoked by IL-4, is the regulatory phenotype that induces phagocytosis and degradation of cell debris and promotes tissue repair and neuronal survival by providing neurotrophic factors [9]. Conversion of M1 to M2 macrophages is important in the initiation and intensity of inflammation in the periphery. The same phenotype change has been observed in microglial cells; however, the link between microglial phenotype change and neuroinflammation remains to be elucidated.

2.3: Astrocytes

Astrocytes, which constitute the majority of the cells in the CNS, are a type of neuroglia cells that function as an important factor in the regulation of synaptic functions and plasticity, modification of neuronal activity, providing supplements of metabolites and growth factors for neurons, sleep homeostasis, modulating the extracellular concentration of ions and, fluid, neurotransmitters, and other factors, and formation of long-term memory [10]. According to astrocytes location that is close to neurons, glial cells, and blood vessels, they are important factors in maintaining the BBB integrity and permeability. Two types of astrocytes are recognized, protoplasmic astrocytes that are resident in the gray matter, and fibrous astrocytes that are found in the white matter. Astrocytes have shown lower secretory functions compared to microglial cells; nevertheless, the crosstalk between different cell types promote the neuroinflammatory response. Reactive astrogliosis is a reaction to brain insults that results in scar formation. Receptors of the complement system and innate immunity, including TLRs, NLRs, scavenger receptors, and mannose are expressed in astrocytes [11]. Astrocytes that are present at the inflammatory milieu, based on the existing factor in the microenvironment, can function to exacerbating the inflammation and tissue injury or function to induce immunosuppression and tissue repair. Sphingolipids, tropomyosin receptor kinase B (TrkB), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), suppressor of cytokine signaling 3 (SOCS3), vascular endothelial growth factor (VEGF), IL-17, and chemokines promote the injury-inducing phenotype. Estrogen, Fas ligand (FasL), glycoprotein 130 (gp130), signal transducer and activator of transcription 3 (STAT3), brain-derived neurotrophic factor (BDNF), transforming growth factor (TGF)-β, and IFN-γ promote the protective phenotype [10,12].

3: Molecular contributors

3.1: Complement factors

Three pathways are recognized for complement system activation (namely, classical, alternative, and lectin-binding pathways), all followed by a common pathway that results in membrane attack complex (MAC) formation. Previously, the CNS was believed to be immunoprivileged; so, as complement factors are produced in the liver, no complement factor exists in the CNS. However, it is currently well established that neurons, astrocytes and microglia express complement factors and receptors. Hence, complement factors exist in the CNS and have both positive and negative effects [13,14]. In physiological condition, complements contribute to clearance of the pathogens in the CNS and to neurogenesis. In pathological conditions and when overactivated, complements may induce detrimental effects. For instance, complement system act as pathological factors in neuromyelitis optica spectrum disorder (NMOSD). In NMSOD, immunoglobulin G (IgG) autoantibodies along with activated complement factors initiate immune responses against aquaporin 4 (AQU-4) in astrocytes and reduce their expression, which results in myelin impairment [15]. The role of the complement system in neuroinflammation was supported according the study of Pittock et al., who showed eculizumab (C5 inhibitor monoclonal antibody) was effective in resolution of symptoms [16].

3.2: Cytokine network

Cytokines are important mediators in neuroinflammation that function as signaling proteins in complex cellular interactions. Even though cytokines are labeled as either proinflammatory or antiinflammatory, in some conditions, the role of the cytokine may alter according to the site of the neuroinflammation within the CNS and the underlying pathologic etiology [17]. While cytokines have intrinsic proinflammatory or antiinflammatory properties, cytokine release also promotes the secretion of further mediators and activation of more signaling pathways. As an example, TNF-α binds to extracellular TNF receptors and induces TNF receptor type 1-associated death domain (TRADD) protein and TNF receptor-associated factor 2 protein (TRAF2), which stimulate the activation of pathways resulting in NF-κB activation, which ultimately leads to inflammation and degeneration. In addition, TRADD and TRAF2 trigger c-jun N-terminal kinase (JNK) pathways that stimulate the activation of some transcription factors, which ends in the regulation of inflammation and apoptosis. Fas-associated protein with death domain (FADD) is also activated via TNF-mediated pathways and provoke the generation of caspase 8, which progress apoptotic and neurodegeneration processes [18,19].

Dysregulated cytokine network is proposed to be involved in many neuroinflammatory conditions. Impaired cytokine network has known to be damaging in classic neuroinflammatory diseases such as multiple sclerosis (MS), when the origin of cytokines are infiltrated immune cells to the CNS. On the other side, the role of the impaired cytokine network, which is originated from CNS tissue resident cells, remains controversial in neurodegenerative diseases and proteopathies [17].

3.3: Chemokines

Despite of low physiological levels in the CNS microenvironment and circulation, chemokines are effective contributors to neuroinflammation. As an example, monocyte chemoattractant protein-1 (MCP-1), which becomes upregulated in prolonged inflammatory condition, recruits more astrocytes and microglia and enhances their chemotactic response. Chemokines may cause neuronal damage and impaired neurogenesis when overactivated [20,21].

3.4: Cyclooxygenase

Eicosanoids are derived from arachidonic acid; the reaction is catalyzed by cyclooxygenase enzyme, which has two identifies isoforms (COX-1 and 2). Prostaglandins and thromboxanes are eicosanoids that have shown inflammatory properties. COX1-mediated pathways have shown proinflammatory features; when COX-1 is expressed in microglia, it enhances prostaglandin synthesis and release. COX-1 pathological effects have been reported in traumatic brain injury (TBI) and neurodegeneration [22,23]. COX-2 is mainly expressed in neurons and contributes to the regulation of synaptic function and formation of memories. Of note, COX-2 has shown antiinflammatory features. Cytokine signaling pathways also interact with cyclooxygenase pathways and affect their activation [24,25].

4: Acute and chronic neuroinflammation

4.1: Acute neuroinflammation

As neuroinflammation could be followed by prolonged inflammation, it is commonly recognized as a chronic condition, as in Alzheimer’s disease (AD) and MS. However, acute neuroinflammation is also identified in some conditions such as postoperative cognitive dysfunction (POCD) and delirium.

POCD happens in some patients after undergoing general anesthesia and surgery. It is associated with memory impairment and cognitive decline, which are suggested to be manifestations of acute neuroinflammation. It is suggested that major surgeries provoke an inflammatory response from different directions. Patients who undergo on/off-pump coronary bypass surgery have shown increased concentrations of TNF-α and IL-6 in plasma samples [26]. Also, C-reactive protein (CRP) level was elevated in those patients, which is proposed to be linked with cognitive decline [27]. Of note, IL-1β is suggested to have an essential role in neuroinflammation-induced cognitive problems [28]. In addition, cytokine-mediated glial secretion of IL-1β is suggested to be involved in hippocampal memory impairment. Although the role of IL-1β is emphasized, a more complex network of cytokines are involved in POCD pathology. Interestingly, antiinflammatory cytokines (such as IL-4) are reported in elevated levels during months after the neuroinflammatory response, which is congruent with POCD resolution that happens months after the anesthesia and surgery [29].

Delirium presents with transient altered psychomotor behaviors (hyper, hypo, or mixed). It is an acute episode of mental status fluctuations associated with disorientation to the environment and attention problems. Acute neuroinflammation is suggested as an important contributor to delirium’s pathology [30]. Of note, in delirium, neuroinflammatory reactions are induced by the same immune and glial cells and via the same signaling molecules as those involved in the pathology of POCD [30].

4.2: Chronic neuroinflammation

Multiple sclerosis is an autoimmune neuroinflammatory disease, characterized by demyelination of axons in the CNS. It is proposed that systemic inflammation is involved in myelin damage [31]; so, the increased risk of disease relapse following infection could be explained. The inflammatory condition in MS is exacerbated and continued via the contribution of adaptive immune system cells, including T cells and B cells [32].

In AD, Formation of amyloid beta (Aβ) plaques and accumulation of hyperphosphorylated tau can be accelerated via increased concentrations of inflammatory mediators. Meanwhile, Aβ and tau facilitate the production of proinflammatory cytokines and inflammatory mediators [33]. Thus, neuroinflammation is an inseparable component in the pathology of AD [34]. It is reported that Aβ trigger the activation of microglia and astrocytes, which in turn, results in further release of cytokines and other inflammatory factors such as nitric oxide (NO) that exacerbates the inflammation [34].

Further evidence supports the role of neuroinflammation in the pathology of MS and AD, which needs to be comprehensively discussed, but the details are out of the scope of this chapter. Also, neuroinflammation is studied in different neurodegenerative diseases such as Parkinson’s disease (PD) and Lewy body dementia.

5: Consequences of neuroinflammation

Prolonged abnormal levels of TNF-α, IL-6, and IL-18 induce early-onset cellular death of the neural progenitor cells, hence inhibiting the neurogenesis process as well as the neural cell differentiation [35]. This process is mainly mediated by proinflammatory phenotype of microglia, while the other phenotype have shown supportive effects in the neurogenesis process [36]. Besides inducing death in neural progenitor cells, prolonged neuroinflammation also induces neuronal death, as many factors necessary for apoptosis are produced in neuroinflammatory pathways (for example, TNF, FADD, TRAIL, etc.) [37,38]. In addition, astrocytes and microglia produce NO, which in excessive amounts, has shown to be neurotoxic. Normal levels of TNF-α and IL-1β have shown to be effective in proper synaptic function and plasticity, proinflammatory mediators have demonstrated damaging effects as well. As an example, overproduction of IL-1β, in association with COX-2 activity, induces synaptic connections loss. Of note, some types of neurological pathologies, including taupathies, occur following synaptic impairment and synaptic connections loss [39]. Furthermore, neuroinflammation trigger the formation of Aβ and tau, in specific conditions, as discussed in previous sections. Therefore, it is majorly involved in the pathology of neurodegenerative diseases. In addition, neuroinflammation influence the microglia priming process [40]. Finally, neuroinflammation is known as one of the main culprits causing the most common manifestation of many neuroimmunological diseases, cognitive dysfunction. However, the underlying mechanisms leading to cognitive dysfunction is complicated and remain to be fully depicted [41,42].

6: Conclusion

As most of the neuroinflammatory diseases are chronic, they impart a huge burden on patients, families, societies, and healthcare system. In addition, in most cases, no definite cure has been recognized so far. Nonsteroid antiinflammatory drugs (NSAIDs), aspirin, 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are also known as statins, and thiazolidinediones have shown promising results in modulating neuroinflammation. In addition, antineuroinflammatory effect of natural compound such as Curcumin, Ginkgo, Naringenin, Quercetin, and Resveratrol have become an interesting area of research. Meanwhile, extensive research is ongoing to elucidate the details of neuroinflammation pathways to provide information for designing novel targeted therapeutic agents.

Although our knowledge about neuroimmunological diseases has increased remarkably during the recent decades, many questions left to be answered and neuroinflammation remains an interesting area of research to be explored.

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Chapter 2: Neuroimmune interactions: From bench to bedside

Christina Peixotoa,b,⁎; Michael Maesc,d,e; Igor Henrique R. Paivaa; Ingrid Prata Mendonçaa; Michel Gomes de Meloa; Eduardo Duarte-Silvaa,f,g,h,⁎,#    a Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Oswaldo Cruz Foundation (FIOCRUZ-PE), Recife, PE, Brazil

b National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil

c Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

d Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

e IMPACT Strategic Research Center, Deakin University, Geelong, VIC, Australia

f Postgraduate Program in Biosciences and Biotechnology for Health (PPGBBS), Aggeu Magalhães Institute (IAM), Recife, PE, Brazil

g Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Recife, PE, Brazil

h Department of Neurology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany

# Current address: Center for Research in Inflammatory Diseases (CRID), Ribeirão Preto Medical School, Department of Pharmacology, University of São Paulo, São Paulo, Brazil

⁎ Corresponding author

Abstract

Neuroimmune interactions comprise the intricate crosstalk that exists between the brain and the immune system, which is only possible because they share a common language. As a result, body homeostasis and proper physiological functions are maintained. Interestingly, when this dialog malfunctions, many diseases emerge, such as neuroinflammatory and neuropsychiatric disorders. However, the knowledge of neuroimmune interactions that take place throughout the body is key to the development of new therapies to treat the aforementioned diseases. Therefore, in this chapter, we discuss in detail how the brain communicates with the immune system and vice versa. Furthermore, we focus on the translational aspects of this crosstalk and how they can be useful in the design of new therapies. Harnessing these interactions is key to understand disease pathophysiology and treatment.

Keywords

Neuroimmune interactions; Cytokines; Neurotransmitters; Microbial metabolites; Hormones; TRYCATs; Vagus nerve; Cell-cell interactions

1: Introduction

In the past, the body was regarded as a compartmentalized, fragmented system. Specifically, the central nervous system (CNS) was considered an immune privileged site sealed from other body parts by the blood-brain barrier (BBB). Furthermore, the immune system was considered to be detrimental to the CNS and the presence of immune cells in the brain parenchyma was always regarded as pathological. However, this old view has been challenged by the advances in different scientific fields, such as neuroscience, immunology, physiology, and even microbiology. In this regard, our current view is that varied bodily systems are interconnected, intertwined with each other, establishing a constant dialog that ultimately aims to coordinate the body homeostasis. Unsurprisingly, this crosstalk is possible only because these systems share molecules and receptors, which enable them to have a common language. For example, cells of the immune system can secrete neurotransmitters, molecules primarily related to the nervous system. Furthermore, immune cells possess receptors for neurotransmitters and neuropeptides, which allow them to respond to these molecules. In a similar fashion, cells of either peripheral or central nervous system secrete cytokines and have cytokine receptors, which are related to the immune system and allow them to respond to immune cues. Furthermore, efferent and afferent nerves constitute another way of communication. Therefore, neuroimmune interactions usually encompass this intricate relationship between the immune system and the brain. However, we should not disregard the influences of the endocrine system and, more recently, the gut microbiota in the nervous and immune systems, which add another layer of complexity to such interactions. The fact that neural and immune cells are often colocalized forming a unit in which they interact and exert important physiological functions, such as tissue homeostasis and protection, led to the proposal of the term neuroimmune cell units (NICUs). Examples of NICUs include, but are not limited to, neuron-mast cell and neuron-macrophage interactions that take place in the gut [1]. Interestingly, disruptions in such crosstalk commonly lead to brain and immune diseases. Harnessing or even targeting neuroimmune interactions may be essential in tackling such diseases and to the development of new therapies. Therefore, in this chapter we explore common neuroimmune interactions/NICUs and discuss possible translational implications of this knowledge.

2: Immune to brain communication

In this section, we describe the mechanisms by which the immune system communicates with the brain and discuss what are the functional consequences of this crosstalk.

2.1: Neuroimmune interactions in the thymus

The thymus is a primary lymphoid organ where T cells complete their development once they leave the bone marrow where the initial phases of T cell maturation occur. Once they are mature, they exit the thymus as either CD4+CD8− or CD4−CD8+ single positive (SP) lymphocytes and gain access to other body sites via the bloodstream. Sympathetic neurons and SNS fibers innervate the thymus and regulate thymocyte development, exerting mainly an immunosuppressive effect. Interestingly, the number of SNS fibers secreting noradrenaline (NORA) increase with age, thus increasing the inhibitory effects on thymopoiesis. Furthermore, NORA content was shown to be elevated in the thymus of aged mice [2]. Interestingly, thymocytes were shown to have a key enzyme in the metabolism of catecholamines (CAs), tyrosine hydroxylase (TH) that converts the tyrosine amino acid into L-DOPA, which is subsequently converted into dopamine (DA), NORA, and adrenaline by different enzymes in the cascade, suggesting that thymocytes can secrete catecholamines and that these endogenous neurotransmitters could modulate their function [3]. CA affects thymus cellularity and function by binding to β- and/or α-adrenoceptors (αAR/βAR) and causes an increase in the number of immature lymphocytes (CD4+CD8+) and decrease in mature lymphocytes (CD4+CD8− or CD4−CD8+), suggesting that CAs can affect thymocyte development and survival [4]. Overall, these neuroimmune changes in the thymus render the host a higher susceptibility to infectious diseases, cancer, or even autoimmunity [4]. Interestingly, using drugs that antagonize the CA effects, αAR/βAR or even TH antagonists, may have neuroimmunomodulatory effects. For example, blocking βAR or TH led to increased apoptosis and diminished proliferation of thymocytes in adult thymic organ [5]. Notably, blocking βAR also augments the number of intrathymic CD4+CD25+ regulatory T cells (Tregs), which are pivotal in the induction of tolerance and prevention of autoimmunity [6]).

The presence of the DA receptors, D1 and D2, as well as vesicular monoamine transporters (VMAT) in the thymus suggests that DA may be another neurotransmitter capable of modulating thymocyte development and function [7]. In fact, administration of DA to mice thymocytes caused apoptosis [8]. Moreover, DA administered during fetal thymus development changes thymocyte proliferation and increases the number of Tregs [9].

Regarding the parasympathetic nervous system (PaNS), vagotomy or vagus nerve stimulation has immunomodulatory effects. After vagotomy, a transient change in the exportation of lymphocytes from the thymus to secondary lymphoid organs was observed. Specifically, immature double positive (DP) and double negative (DN) T lymphocytes were abundant in spleen and lymph nodes after 24 and 48 h section of the vagus nerve at the cervical level. However, the number of single positive (SP) lymphocytes was decreased [10]. In contrast, when the right vagus nerve was sectioned, a decrease in the number of lymphocytes exported from the thymus was observed. Interestingly, stimulation of the vagus nerve produced the opposite effect [11].

It is important to note that either exogenous or endogenous neurotransmitters may trigger an even more complex network inside the thymus. This network is also composed of intrathymic hormones or even peptides produced and released by the thymus (thymulin and thymosin) that may be modulated by endogenous or exogenous cytokines, hormones, and neurotransmitters. This intricate network is essential for thymocyte development, survival, and function and is altered in disease states [12]. This network composed of intrathymic molecules (hormones, cytokines, neurotransmitters, and peptides), which interact with peripheral molecules (hormones, cytokines, and neurotransmitters), is known as neuroendocrine-immune (NEI) interactions [13]. Therefore, the thymus is a complex organ where complex interactions between the endocrine, immune, and nervous systems take place, influencing not only immunity, but also behavior [14].

Neurotrophins, a class of molecules primarily related to the nervous system that regulates neurogenesis and neuronal survival, plays a key role in the maturation of T cells. For example, brain-derived neurotrophic factor (BDNF) modulates thymocyte development. In BDNF knockout (KO) mice, increased levels of double-negative (DN) thymocytes and decreased numbers of peripheral T cells were observed, showing that this factor is required for thymocytes to fully complete its development [15]. Furthermore, nerve growth factor (NGF) also plays an important role in the thymus since it can be secreted by thymocytes and act on thymic epithelial cells (TECs), causing trophic effects [16].

2.2: IL-4 and memory

The CNS is separated from the peripheral area by a very selective barrier, the BBB. Like other cells, immune cells are not able to access the CNS. However, a region called choroid plexus and ventricular area is more permeable and allows cerebrospinal fluid (CSF) cells, located in the subarachnoid region, to penetrate the CNS. In the CSF, we can find many leukocytes, most of them are memory T cell type [17,18].

This neuroimmune integration is related to several pathophysiological substrates of neuropsychiatric diseases. It is already known that the presence of proinflammatory cytokines may damage the BBB and, consequently, lead to impairments in brain functions. Among the main proinflammatory cytokines, IL-18, IL-6, IL-12, and TNF-α, in conditions such as stress, depression, senile aging, Alzheimer’s disease (AD), Parkinson’s disease, etc., can cause neuroinflammation and neuronal death [19,20]. On the other hand, more recent studies have shown the beneficial modulatory effects of the immune system in animal models of senility, AD, and in learning and memory, demonstrating the importance of the adaptive immune system in neurophysiological functions and in the regulation of higher cognitive functions [19,21–24]. This modulatory function involves, above all, CD4+ T cells, which are able together with IL-4, to regulate neural plasticity and cognitive function [17]. The CD4+ T cell is a type of lymphocyte called T helper (Th) cell, which is part of a special subset that works to prevent or limit immune responses and can be divided into Th1 or Th2 cells. IL-4, on the other hand, is the main cytokine of the Th2 subgroup and functions both as an inducer and as an effector cytokine of these cells. IL-4 has several actions, acting mainly as an immunoregulatory cytokine [25].

It is known that in the brain IL-4 antagonizes the deleterious effects of proinflammatory cytokines on astrocytes and neurons, in addition to promoting the expression of an astroglial phenotype that supports cognitive function, as it promotes an increase in the production of astrocytic brain-derived neurotrophic factor (BDNF), which is important for hippocampal neurogenesis and its functions. Nevertheless, little is known about how IL-4 stimulates neurons and oligodendrocytes [17]. Since IL-4 modulates the production of neurotrophins, this cytokine may have affect higher cognitive functions, including memory and learning [17]. Learning processes refer to changes in behavior that result from the acquisition of knowledge from the environment. Memory is the process by which this knowledge is encoded, stored, and later evoked. Among the structures involved in the learning and memory processes, the hippocampus stands out as crucial player, a bilateral structure located in the mesial temporal lobe, responsible for encoding, storing, and evoking the acquired information [26]. When acquired, memory can be stored and consolidated in a way that allows it to be evoked after long periods. This process involves molecular and cellular changes, called long-term potentiation (LTP). The LTP process can be delayed by proinflammatory cytokines, which may compromise memory consolidation [17,26].

Likewise, adaptive immune deficiency in mice is directly related to reduced cognitive ability in spatial learning and memory tasks [27]. T cell deficiency, demonstrated by the administration of anti-CD3 antibodies, results in cognitive damages in animal models [28]. On the other hand, a study with rodents showed that learning and memory activities were followed by an increase in the number of meningeal T cells in animal models. Another study that trained mice on the Morris Water Maze (MWM), a test that uses hippocampal-dependent visuospatial memory skills, demonstrated an increase in IL-4 levels by meningeal T cells when compared to control animals, which were not trained in MWM, confirming the relationship between IL-4 and the learning and memory processes [17]. In the same MWM test type, mice that did not have T lymphocytes presented cognitive deficits in learning tasks, in addition to a reduction of hippocampal neurogenesis [29]. These T cells present an activation phenotype and express high levels of IL-4, suggesting a possible molecular link with the CNS. In mice without T cells, meningeal myeloid cells adopted a distorted proinflammatory phenotype, expressing high levels of TNF-α and IL-12, which resulted in an inflammatory phenotype and cognitive deficits [17,27]. Such findings reinforce the interaction of the adaptive immune system, specially IL-4, and the CNS being capable of modulating higher cognitive functions, particularly learning behavior and memory formation, confirming the need for the integrity of the immune system for physiological functioning of neuropsychic functions, in addition to supporting possible therapeutic treatments in prevention and cognitive rehabilitation.

2.3: Cytokines, T cell and learning, cognition and behavior

So far, interactions between the brain and the immune system are well known and accepted. We can already understand how T cells interact with the CNS by allowing an integration and modulation of physiological and/or pathological functions, thus regulating cognitive functions such as learning and memory. Associated with the immune system, it is also possible to integrate the CNS and immune system with the endocrine system, mediated by the hypothalamus-pituitary-adrenal axis (HPA) [30,31].

Although the immune processes within the brain are not identical to those that occur in the peripheral area, the brain has its own immune cells, such as microglia, capable of producing cytokines and other inflammatory molecules in responses to changes in homeostasis in a similar way to immune cells from the surroundings. In addition to microglia, other cells of the CNS participate in the synthesis of cytokines and chemokines and in the expression of their receptors, such as perivascular macrophages, astrocytes, endothelial cells, oligodendrocytes, and the neuron itself. All these events occur in physiological processes and in response to aggressions/diseases [30–32]. In addition to these resident cells, there are several pathways by which various factors derived from the periphery can reach and affect the brain, among them, include the products of the autonomic nervous system and the HPA axis, and cytokines that can cross the BBB [31,32].

Cytokines have autocrine and paracrine actions in local tissues, in addition to hormonal activity when released into the bloodstream and then signaling in the CNS. Many types of cytokines are well known, such as TNF-α, IFN, IL-1 to IL-26, EGF, colony-stimulating factor (CSF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), macrophage inflammatory protein (MIP), and insulin-like growth factor (IGF). Cytokines are generally classified as pro- or antiinflammatory in terms of the immune response. However, many cytokine actions are pleiotropic and depend on the environment in which they are inserted [31,33,34].

Cytokines have neuromodulatory properties during inflammatory processes in the brain, but they also have constitutive activities in healthy brain tissue, regulating behaviors, and homeostatic mechanisms such as sleep and wakefulness, learning and memory, and energy metabolism, as discussed in the previous section on the role of T cells and IL-4 in learning and memory. On the other hand, many studies demonstrate the relationship between major depressive disorder (MDD), Parkinson’s disease (PD), AD, and other neuropsychiatric conditions with neuroinflammatory processes, which compromise neuronal integrity and, consequently, cognitive behavior and functions