Diabetes and Breast Cancer: An Analysis of Signaling Pathways E-Book
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- Herausgeber: Bentham Science Publishers
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- Sprache: Englisch
Diabetes and Breast Cancer: An Analysis of Signaling Pathways is an in-depth monograph that explores the cross-talk between diabetes and breast cancer. The edited volume sheds light on the complex relationship between the two diseases by explaining the critical regulatory signaling in their progression.
Topics covered in the book include the genetic similarities between type 2 diabetes and breast cancer, signaling pathways for breast cancer cell invasion and migration (including fat cadherin, Wnt signaling and IGF signaling).and research on associated conditions such as neuropathy, inflammation, hypoxia and obesity. A summary of new natural medicines for targeting these diseases is also included.
Scholars, academicians, and professionals in medicine and pharmaceutical research who want to gain a better understanding of the complex interplay between diabetes and breast cancer will learn about the underlying biochemical mechanisms, pharmacogenomics, and precision medicine approaches for the simultaneous management of both diseases
Key Features
- Gives a comprehensive overview of the cross-talk between diabetes and breast cancer
- Covers information on multiple signaling pathways and associated conditions
- Provides insights contributed by biomedical experts with detailed references
Readership
Research scholars, academicians, healthcare professionals (endocrinologists, oncologists, internal medicine specialists) and R&D professionals in pharmaceutical chemistry.
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Seitenzahl: 459
Veröffentlichungsjahr: 2024
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FOREWORD
I am happy to introduce Dr. Asis Bala, a valued scientist, for his book on “Diabetes and Breast Cancer: An Analysis of Signaling Pathways”, which is a real advancement in the field.
PREFACE
Research has shown that breast cancer patients with diabetes experience worse clinical outcomes compared to those without diabetes, indicating a possible link between diabetes and breast cancer cell progression and migration. The exact reasons for this association are still being studied, but it is believed that factors such as hyperglycemia and hyperinsulinemia in type 2 diabetes may play a role. To better understand this link between diabetes and breast cancer, it is important to thoroughly investigate the signaling pathways involved. By doing so, biomedical scientists may be able to develop more effective treatments that target these mechanisms. The main focus of this book is to provide a detailed analysis of the signaling cross-talk between diabetes and breast cancer, with the goal of facilitating future drug development and improving patient outcomes. This book elucidates the critical signaling mechanisms and signaling Analysis to cross-talk between Diabetes and Breast Cancer. The key features include-
- Explains the role of critical regulatory signaling for Breast cancer progression during diabetes and obesity-associated conditions.
- Covers and explores the Genetic similarity between type 2 Diabetes and breast cancer.
- Systematically explains the signaling analysis to insulin for breast cancer cell invasion and migration and explores the possible pharmacological target for its concomitant management.
- Outline the Pharmacogenomics and Precision medicine approaches in relation to Diabetes and Breast Cancer.
This book is designed to provide valuable insights into the complex signaling mechanisms that link diabetes and breast cancer. This book is a useful resource for biomedical scientists in academia, the bio-pharmaceutical and biotechnological industries, as well as individual researchers and PhD scholars. By delving into the intricacies of this cross-talk, the book aims to facilitate the development of future drugs that can target these signaling pathways more effectively. Furthermore, as the first of its kind, this book will serve as a go-to reference for academics and students seeking a comprehensive understanding of this crucial field.
ACKNOWLEDGEMENT
It brings me great joy to express my appreciation for the numerous requests that have been sent my way from fellow researchers and academics to write a book on Diabetes and Breast Cancer: An Analysis of Signaling Pathways. I am deeply grateful for their unwavering inspiration, support, and moral encouragement.
This book would not have been possible without the tireless efforts of many researchers, and I am pleased to acknowledge the contributors who have willingly taken on the many demands placed upon them. We had the pleasure of partnering with Bentham Science Publishers, and we cannot thank them enough for their invaluable support. They approached the task with efficiency and perfection.
I would also like to extend a special thanks to Prof. Ashis Kumar Mukherjee, Director, Institute of Advanced Study in Science and Technology (IASST) and Department of Science & Technology (Govt. of India) for the continuous encouragement and support.
Lastly, I am grateful to my family for granting me the time and space needed to work on this book.
List of Contributors
Interplay between Diabetes and Breast Cancer: A Brief Report
Susmita Patra1, #,Ratul Chakraborty2,3, #,Motlalepula G. Matsabisa4,Asis Bala2,3,*Abstract
Cancer and diabetes are two of the most prevalent and complicated diseases. Several epidemiological studies have found a link between type 2 diabetes and an increased risk of breast cancer. This chapter aims to highlight the advances in understanding the mechanisms that connect diabetes and breast cancer. Alterations in glucose metabolism, hyperinsulinemia, insulin resistance, changes in the hormonal environment, and substrate availability create a metabolic environment that is particularly favourable for the growth of tumours. Therefore, it is vital to understand the correlation between diabetes mellitus and breast cancer. A precise analysis of these relationships could help in finding biomarkers that can predict disease risk and prognosis, and aid in selecting appropriate, evidence-based diagnostic and therapeutic approaches.
INTRODUCTION
Chronic diseases in the twenty-first century are an existential threat to human health due to dietary overload or excessive energy consumption [1]. In developed nations, the prevalence of type 2 diabetes has been gradually increasing for decades and now affects 10% of the population [2]. Diabetes mellitus is regarded as a global pandemic and the tenth leading cause of mortality globally. Studies have shown that diabetes is associated with the development of several types of cancers, including breast cancer. Women with diabetes are 23% more likely to develop breast cancer than non-diabetic women [3]. Type 2 diabetes brings about changes to cellular and overall metabolism, which foster an environment that promotes the progression of breast cancer [4]. Several pathways that connect type 2 diabetes to breast cancer, such as the activation of insulin-like growth factor pathway, hyperinsulinemia, high estrogen levels, higher leptin quantities, and lower adiponectin values, activation of AKT pathway, immune responses such as elevated levels of proinflammatory cytokines like tumor necrosis factor-a (TNF-α) have been identified through multiple studies [4-6]. This chapter provides an overview of the key metabolic changes associated with type 2 diabetes and how breast cancer cells use cellular metabolism modifications to promote abnormal growth and proliferation. These findings offer insights into the comorbid situation and may be used to design several therapeutic approaches for treating breast cancer in diabetic patients in the near future. The development of breast cancer during the diabetic condition is influenced by several key factors.
Insulin Resistance
One of the main characteristics of type 2 diabetes is insulin resistance [7]. The hormone insulin, produced by the pancreatic β-cells, helps to regulate blood glucose levels by facilitating glucose absorption and storage [7, 8]. Insulin binds to the insulin receptor (IR), which activates the glucose transporter 4 (GLUT4) and facilitates glucose uptake into tissues like skeletal muscle, adipose tissue, and liver. Insulin resistance is such a condition when a certain concentration of insulin is present but has a lower biological impact than anticipated [9]. Insulin primarily affects metabolism and cell growth by binding to the insulin receptor (IR) and activating its tyrosine kinase activity, leading to the phosphorylation of the receptor substrate [10]. When the IR/PI3K/Akt signalling pathway is activated, mTOR is also phosphorylated and activated. The activation of this pathway encourages cancer cell survival, proliferation, invasion, migration, differentiation, angiogenesis, and metastasis. Additionally, the activation of the IR/PI3K/Akt signalling pathway triggers -catenin translocation into the nucleus and raises vascular endothelial growth factor (VEGF) levels, which affects the behaviour of tumour cells [7-10].
Inflammatory Cytokines
Type 2 Diabetes Mellitus (T2DM) is often characterized by chronic low-grade inflammation that leads to an increase in local and systemic cytokine levels, including Interleukin 6 (IL-6), C-reactive protein (CRP), tumour necrosis factor (TNF)-α, and adiponectin [11, 12]. Cytokines like IL-6 may substantially affect the development of cancer through signaling cascades [13, 14]. The signalling pathways of IL6, Janus kinase 2 (JAK2), and Signal Transducer and Activator of Transcription 3 (STAT3) are essential for the invasion and metastasis of malignant tumours [13]. The JAK2/STAT3 pathway is required for the development of breast cancer (BC) cells, which are human CD44+CD24- stem cells. JAK2/STAT3 is linked to the development of tumour cachexia and can cause a systemic inflammatory response [14]. IL-6 activates JAK2, one of the non-receptor tyrosine kinases, after binding to membrane receptors these phosphotyrosine residues serve as docking sites for the recruitment of the STAT3 protein, which functions as a cellular IL-6 mediator [12]. After activation, the oncogene STAT3 reacts to extracellular inputs and the JAK2 pathway. The two STAT3 monomers tyrosine phosphorylate, form a dimer, travel to the nucleus, attach to the target gene of STAT3-specific DNA response element, and trigger transcription of the gene. Thus, IL-6 promotes the activation of the JAK2/STAT3 pathway in its downstream cascade, which helps to promote carcinogenesis by controlling angiogenesis, cell cycle progression, and immune system escape of tumour cells [13]. IL-6 is also produced by tumour cells when STAT3 is overactive, creating a positive feedback loop. The abnormal activation of JAK2/STAT3 signaling mediated by IL-6 is strongly associated with the metastasis of human breast cancer [13, 14].
Oxidative Stress
Oxidative stress or an altered redox system develops from the excessive production of reactive oxygen species (ROS) or reactive nitrogen species (RNS) that aren't eliminated by endogenous antioxidants [15]. Although these ROS usually participate in cell signaling, high levels of superoxide radical (O2), hydroxyl radical (HO), and nonradical hydrogen peroxide (H2O2) can cause damage and harm to cells and tissues [15, 16]. Malondialdehyde (MDA), which is an indication of free radical-mediated lipid peroxidation, has been linked to an increase in antioxidant enzymes in people with type 2 diabetes (T2D) [17]. This connection may result from an adaptive response to prooxidants in the diabetic state [16, 17]. In this favorable environment, ROS can trigger carcinogenesis by acting as chemical effectors in the setting of a redox imbalance [17, 18]. ROS plays a significant role in the epigenetic regulation of cancer cells because they have been linked to both aberrant DNA hypermethylation and hypomethylation and have been demonstrated to alter DNA methylation patterns during malignant transformation and cancer progression [15-18].
Hyperlipidemia
Dyslipidemia is a common characteristic of type 2 diabetes mellitus. The condition is marked by high levels of triglycerides, low levels of HDL cholesterol, and excessive amounts of low-density lipoprotein cholesterol [19]. High levels of NEFAs (non-esterified fatty acids) and cholesterol trigger intracellular signaling pathways, such as the Akt/mTOR and Akt/GSK3-/-catenin oncogenic pathways, by acting as signaling molecules [20].
In ER-positive breast tumors, 27HC (27-Hydroxycholesterol) acts as an ER (Estrogen Receptor) agonist to activate ER-related signaling pathways, such as the Akt/mTOR pathway or Akt/GSK3/-catenin, thereby promoting cell proliferation and protein synthesis [21]. Increased serum NEFA levels trigger protein kinase C (PKC), which in turn activates the oncogenic pathways Akt/mTOR and Akt/GSK3/-catenin. Additionally, NEFAs contribute to the production of ATP via the oxidative route, as well as the manufacture of membrane lipids and signaling molecules that support the development and proliferation of cancer cells [21, 22].
Receptor for Advanced Glycation end Products (Rage)
Advanced glycation end products (AGEs) are physiologically produced chemical molecules that are biologically active and produce highly reactive aldehydes that bond covalently with proteins [23]. Patients with type 2 diabetes have an increased rate and severity of AGE accumulation in their skin and serum. The biological effects of AGEs are primarily mediated by binding to the immunoglobulin superfamily transmembrane protein receptor for advanced glycation end-products (RAGE), which is expressed in both normal and malignant cells. RAGE activation may contribute to genomic instability and DNA damage, as well as proliferative, angiogenic, and migratory responses accompanied by malignant features and a worse prognosis [24]. RAGE serves as a crucial mediator, linking chronic inflammation to thedevelopment of cancer.
Hyperinsulinemia
Hyperinsulinemia is a chronic condition that is present both in type 1 and type 2 diabetic patients. In experimental mice, researchers discovered that insulin facilitated the growth of cancer. Insulin acts through its receptor and the related type I IGF receptor (IGF-IR) to have metabolic and mitogenic effects [25, 26]. The IGF-1 system significantly influences the maintenance and functioning of mammary glands [27].
Insulin activates the insulin receptor (IR) and postreceptor signalling by binding to the IR binding site and causing conformational changes and tyrosine phosphorylation of the receptor b subunit, as well as the recruitment of intracellular molecules via a complex network of redundant signals. In a simplified model, the PI3K/Akt pathway largely promotes glucose uptake and metabolic activity, while the postreceptor MAPK pathway principally mediates the mitogenic effect of insulin [28, 29]. However, insulin resistance primarily affects the metabolic route, which leads to compensatory hyperinsulinemia. This overstimulates the mitogenic pathway and encourages cell proliferation. When insulin levels are extremely high, it can also activate the IGF-I receptor, further encouraging cell growth.
Hyperinsulinemia upregulates hypoxia-inducible factor-1a (HIF-1a), a transcription factor considered a master regulator of hypoxic gene expression and a promoter of angiogenesis. This contributes to leptin overexpression, which in turn upregulates VEGF, a characteristic of the growth of malignant tumours [30].
Hyperglycemia
One of the most noticeable clinical indications of diabetes is high blood sugar. Cell proliferation requires a significant amount of energy, leading to the theory that “glucose fuels cancer” by providing energy for rapidly dividing cells, as evidenced by the high levels of glucose absorption during PET scans. Rather than producing ATP efficiently, cancer cells utilize the inefficient process of glycolysis to meet their energy needs, allowing them to metabolize nutrients in a way that promotes growth [31]. Hyperglycemia has been found to activate the HIF1 pathway by increasing the expression of the HIF1-gene, leading to an antiapoptotic response and the activation of oncolytic pathways. The Hypoxia-Inducible Factor (HIF)-1 is a vital protein complex in the body's response to low oxygen levels. Due to its angiogenic properties, HIF-1 promotes the survival and growth of cancerous cells [32]. A study conducted on rat pancreatic beta cells found that high glucose levels cause an increase in oxygen consumption, leading to hypoxia and HIF1 activation, which is linked to a gradual decrease in beta cell function [33]. Hyperglycemia can cause endothelial dysfunction and uncontrolled neoangiogenesis in diabetes. Similarly, high blood sugar levels can promote angiogenesis in tumors by increasing microRNA-467, which inhibits the antiangiogenic protein thrombospondin-1. Neoangiogenesis in cancer may promote the development of malignancy [34].
CROSSTALK PATHWAYS BETWEEN DIABETES AND BREAST CANCER
Research has shown that diabetes and breast cancer share multiple pathways. Insulin plays a crucial role in this crosstalk by binding to the insulin receptor and triggering the PI3K-AKT and MAPK pathways, as well as the HIF1 signaling via the mTOR pathway [35] as shown in Fig. (1). HIF1 signaling upregulates GLUT1 and GLUT3, which in turn regulate metabolism, VEGF, which regulates angiogenesis and aids in cell survival, and c-Myc and IGF2, which encourage cell proliferation. Although the PI3K-Akt and MAPK pathways are downstream of IGFR, which is directly associated with cancer, PTEN raises the PI3K-Akt and MAPK signaling pathways and increases the risk of cancer in patients with diabetes [36].
Fig. (1)) Crosstalk Pathways between Diabetes and Breast Cancer: The role of hypoxia and insulin signaling in breast cancer cell proliferation and migration are shown schematically.GENETIC INFLUENCES BETWEEN T2DM AND BREAST CANCER
Through a bioinformatics system approach, in a very recent study, it was found that certain genes are differentially expressed (DE) and proteins are inappropriately expressed in T2D individuals, which can lead to the development of breast cancer in females. G0S2, ADCYAP1R1, EDNRB, NPR2, AADAC, ACTG2, SOCS3, MT1JP, FTL, LINC02185, CPA1, CXCL3, MTRNR2L2, DHRS9, and C7 were the most notable down-regulated genes, while CFB, C4A, ANXA9, FBP1, SLC44A4, UNC5B, MFAP2, FGB, GAD1, C4B, FSTL4, FAIM2, SMIM22, SERPINA6, SMPDL3B, EDN2, WFDC2, CST2, PLEKHB1, SPP1, SERPINA1, STK19, PEG10, NPY1R, ANKRD1, HABP2, VTCN1, PYY, CEACAM7 and PALM3 were the most commonly up-regulated genes in female breast cancer and T2D. These DEGs were identified based on their association with the ER signaling pathway, which is crucial for the growth and development of breast cancer with ER+ [37]. The role of microRNA and hypoxia in oncogenic development is shown in Fig. (2).
Fig. (2)) The role of microRNA and hypoxia in oncogenic development.CONCLUSION
Here, we represent the relationship between diabetes and cancer. Diabetes can impact breast cancer prognosis by affecting insulin levels, growth factors, and inflammatory markers, which may promote breast cancer development. It has recently become crucial to comprehend the connection between metabolic disorders and cancer. By precisely examining these relationships, biomarkers that indicate the likelihood of a disease or its prognosis can be established. In this work, we have summarized the most recent studies regarding the relationship between diabetes and breast cancer. This work will enable researchers as well as clinicians to plan future studies and investigate other biomarkers as possible targets for the pharmacological development and medications for diabetes-associated breast cancer.
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Sreemoyee Sensharma1,Nilakshi Thakuria1,Subrata Pramanik1,2,*Abstract
The understanding of the complex relationship between the immune and nervous systems has significantly evolved in recent years. It is now recognized that the inflammatory response and interactions between these two systems play crucial roles in the development and progression of neurodegenerative diseases and injuries. The immune and nervous systems are intricately connected, with bidirectional communication pathways that allow them to influence each other's functions. This cross-talk is mediated by various signaling molecules including cytokines, chemokines, and neurotransmitters. Neuropathic pain is a debilitating condition that arises as a result of damage or dysfunction in the central nervous system (CNS) or peripheral nervous system (PNS). Neuropathic pain is a common pathological symptom of cancer and diabetes. Neuropathic pain can be generated by resulting injury to peripheral or central neurons through various neural pathways, ion channels, receptors, and neurotransmitters. In this article, we elaborate on the recent progress in the understanding of mechanism of the neuroinflammation. First, we provide current knowledge of neuroinflammatory molecules and their association with neuroinflammation. Subsequently, we describe recent advances in the understanding of the pathophysiology of neuropathic pain in PNS and CNS, emphasizing breast cancer and diabetes. Finally, we highlighted the current challenges of molecular understanding and diagnosis regarding targeted therapies for the treatment of neuropathic pain.
INTRODUCTION
The International Association for the Study of Pain has characterized pain as “a disagreeable sensory and emotional encounter linked to real or potential harm to bodily tissues” [1]. Neuropathic pain is a term used to describe pain that results
from damage or disease affecting the somatosensory system. It encompasses a diverse range of pain syndromes and can be associated with a wide array of both peripheral and central nervous system disorders [2]. The mechanisms underlying neuropathic pain in these conditions are multifaceted and frequently involve neuroinflammatory processes. It can manifest in various disease states, including cancer and diabetes, and is characterized by persistent and often severe pain that is challenging to manage [3].
Cancer-related neuropathic pain is a frequently encountered issue, stemming from either the disease itself or as a result of the acute or chronic consequences of cancer treatment. For instance, chemotherapy-induced peripheral neuropathy affects approximately 90% of patients undergoing neurotoxic chemotherapy [4]. As per the data from the International Diabetes Federation, there are currently 382 million people worldwide suffering from diabetes [5]. Diabetes is recognized as one of the primary causes of diabetic neuropathy [6], a common complication characterized by nerve damage resulting from prolonged hyperglycemia, whereas in cancer, neuropathic pain can result from tumor-related nerve compression or infiltration, as well as the adverse effects of cancer treatments, such as chemotherapy-induced peripheral neuropathy [7].
Neuroinflammation is a specific term used to describe inflammatory conditions occurring within the nervous system. This phenomenon can lead to the significant issue of neuropathic pain, a condition characterized by pain resulting from damage or malfunction in the nervous system [8]. The neuroinflammatory mechanisms contributing to neuropathic pain in these conditions involve the activation of glial cells, the release of pro-inflammatory cytokines, and alterations in neuronal function [9, 10]. These processes create a state of heightened sensitivity within the nervous system, leading to the development and maintenance of neuropathic pain. Understanding these neuroinflammatory mechanisms is crucial for developing targeted therapies that can alleviate neuropathic pain and improve the quality of life for patients with cancer and diabetes. This brief overview sets the stage for a more in-depth exploration of these mechanisms in the context of neuropathic pain associated with cancer and diabetes.
NEUROINFLAMMATION
Neuroinflammation is a type of broad immune response, majorly of the CNS, involving cells like microglia and astrocytes. Increasing evidence suggests that neuroinflammation is one of the fundamental causes of several CNS diseases including Alzheimer’s disease (AD), Parkinson’s Disease (PD), and Multiple sclerosis (MS) [11]. Nonetheless, there is a debate surrounding whether neuroinflammation plays a harmful or advantageous role in the development of CNS diseases [12, 13]. This hinges on the production of pro-inflammatory mediators versus anti-inflammatory mediators and/or growth factors during various stages of neuroinflammation. Neuroinflammation increases the susceptibility to cancer development and encourages all phases of tumorigenesis. Specifically, pro-tumorigenic inflammation supports cancer by impeding antitumor immunity, influencing the tumor microenvironment (TME), and delivering direct signals and functions that promote tumor growth to epithelial and cancer cells [14].
Neuroinflammation can be observed in both PNS, comprising peripheral nerves and ganglia, and the CNS, comprising the spinal cord and brain. It is marked by the infiltration of leukocytes and elevated production of inflammatory mediators within these areas [15, 16]. Neuroinflammation represents a localized type of inflammation, making it more efficient at triggering and maintaining pain compared to systemic inflammation. Emerging targets include chemokines, which facilitate interactions between neurons and glial cells, lipid mediators that act on neurons and glia to resolve inflammation, as well as other molecules that control neuroinflammation, such as proteases and WNT signaling molecules [14]. However, its clinical detection remains challenging, and further studies are necessary to determine the cellular prerequisites that modulate inflammation [14].
Neuroinflammatory Molecules
The blood-brain barrier (BBB), which is the endothelial layer, plays a pivotal role in comprehending how peripheral inflammation can lead to prolonged and detrimental neuroinflammation [10]. Initially, it was believed that inflammatory cytokines and other proteins were too large to access the brain from the bloodstream, but over the past two decades, various transport mechanisms have been discovered. BBB active transport systems have been observed facilitating the passage of tumor necrosis factors (TNFs) and interleukins (ILs) into the brain [17]. Certain regions with incomplete barrier properties at the blood-brain interface, known as circumventricular organs, serve as concentrated sites for cytokine transport [18]. Notably, cytokines like TNFα, IL-6, IL-1β, and others can compromise the integrity of the BBB, making it more permeable and allowing the entry of immune cells into the brain [19, 20]. Cytokine levels are known to modulate BBB permeability by affecting the tight junctions in endothelial cells within the brain's vasculature [21]. High cytokine levels can upregulate inflammatory cytokines and COX-2 transcription in the endothelium [9]. Damage to essential tight junction proteins, such as occludin, can lead to increased tight junction permeability, potentially affecting their interaction with the cell cytoskeleton. Furthermore, peripheral cytokines can stimulate the vagus nerve, directly influencing the CNS and inducing sickness behavior [22], representing an intriguing avenue for the translation of peripheral inflammation to neuroinflammation.
The movement of immune cells across the BBB is also influenced by humoral factors such as chemokines. For instance, chemokine (C-C motif) ligand 19 (CCL19) and CCL21 facilitate T cell adhesion to the BBB, while chemokine (C-X-C motif) ligand 12 (CXCL12) may play a crucial role in reducing T cell infiltration (Fig. 1) [23]. Many of these humoral factors are produced by astrocytes, and the upregulation of molecules released by these glial cells can have significant effects on the BBB’s integrity. For instance, bradykinin can trigger the release of IL-6 from astrocytes during inflammation [24].
Fig. (1))Inflammatory molecules in neuroinflammation. Schematic representation of neuroinflammatory mediators initiated by damaged neurons, microglia, astrocytes, and infiltrating macrophages. Key mediators include COX-2, ATP (adenosine 5′-triphosphate), TNFα, IL-1β, IL-6, IL-2, CXCL1, reactive oxygen species (ROS), etc. These mediators contribute to the neuroinflammatory response in the CNS.Microglial cells, the resident macrophages of the CNS, play a pivotal role in neuroinflammation. In response to cytokines and other signaling molecules in acute inflammation, microglia transition from an inactive, ramified state to an activated phagocytic state, releasing pro-inflammatory mediators in the process [14]. In cases of chronic neuroinflammation, these cells can remain activated for extended periods, releasing significant amounts of cytokines and neurotoxic molecules that contribute to long-term neurodegeneration [25]. Macrophages can be activated in various ways, falling along a spectrum categorized into M1 or M2 activation. M1, or classically activated, macrophages are triggered by interferon (IFN)-γ and TNF, playing a role in an aggressive first-line immune response. In contrast, M2, or activated macrophages, typically stimulated by IL-4, are involved in wound healing and macrophage response regulation. Shifting from M2 to the pro-inflammatory M1 state can significantly impact the intensity and progression of peripheral inflammation, potentially affecting microglia in the CNS, though limited information is available on the relationship between microglial activation states and neuroinflammation. Astrocytes constitute the other family of glial cells that release pro-inflammatory signaling molecules such as TNFα when stimulated in the cortex and midbrain [26]. These cells also play crucial roles in synaptic function and regulation. Although microglia exhibit more significant inflammatory cytokine release [27], the collective glial response can profoundly influence the neurodegeneration observed in dementia [28, 29]. A dynamic interplay exists between BBB endothelial cells, glia, and neurons [30], and it is likely that a neuroinflammatory response from one cell type directly impacts another.
Toll-like receptors (TLRs) are essential signal transduction proteins in the innate immune system and the inflammatory response. These pattern recognition receptors become activated upon detecting foreign microbes, initiating downstream signaling pathways. One significant example is the MyD88 pathway, which stimulates the protein kinase IRAK-4 to initiate a signaling pathway that regulates gene transcription. TLR-4 is particularly important as it is induced by lipopolysaccharide (LPS), an endotoxin found in the outer membrane of gram-negative bacteria. Through TLR signaling, LPS induces systemic inflammatory response syndrome (SIRS) and sepsis in animals, with humans being particularly sensitive. This pathway is frequently employed to induce an inflammatory response in animal models. TLR-4 activation leads to the release of TNFα and IL-1β and plays a central role in pro-inflammatory signaling [14]. Astrocytes and microglia express various TLRs that activate these cells, initiating neuroinflammatory responses. Microglia express both major histocompatibility complex classes, MHC class 1 and MHC class 2, which are primarily involved in responding to infectious diseases but are believed to have a role in the development of neuroinflammation [31].
Cytokines are signaling proteins that orchestrate neuroinflammation, either intensifying or mitigating it. Pro-inflammatory cytokines like IL-1 and TNFα, which are biologically similar, play a central role in pathological inflammation and disease progression. Conversely, several cytokines, including IL-4, are predominantly anti-inflammatory [32]. It’s important to note that pro- and anti-inflammatory distinctions cannot always be rigidly applied to specific cytokines in all instances of normal physiology and disease, as the effects of a signaling molecule can vary depending on its location within the CNS and in the context of disease (Fig. 1).
The initial release of cytokines can trigger the production of other signaling molecules, as illustrated by IL-6 activating T cells and stimulating the production of other inflammatory markers, including C-reactive protein (CRP) and fibrinogen [33]. When TNFα binds to the extracellular TNF receptor-1, it initiates several signaling cascades that impact gene transcription. One common cascade leading to inflammation and degeneration involves the recruitment of Tumor Necrosis Factor Receptor Type 1-Associated Death Domain Protein (TRADD) and TNF receptor-associated factor 2 protein (TRAF2), which activate the transcription factor nuclear factor kappa B (NF-κB). These proteins also activate c-junction N-terminal kinase (JNK) pathways, which, in turn, activate various other transcription factors that regulate apoptosis and inflammation [34]. TNF signaling can also directly induce apoptosis through the Fas-Associated protein with Death Domain (FADD)-mediated production of the enzyme Caspase-8, strongly associated with apoptosis and neurodegeneration [35]. When IL-1β binds to the IL-1 receptor complex, it initiates several signal transduction cascades, particularly the mitogen-activated protein kinase pathway (MAPK) [36]. p38 MAPK, like JNK, is a stress-activated protein kinase, and its activation leads to various pro-inflammatory responses and the production of IL-8 and IL-6 [33]. While their physiological concentrations within the CNS are quite low, levels of certain chemokines, such as monocyte chemoattractant protein-1, are significantly upregulated in chronic neuroinflammation [37]. These molecules play a role in the upregulation and chemotaxis of astrocytes and microglia in response to an inflammatory stimulus, potentially disrupting neuronal function and negatively impacting neurogenesis [14].
The complement cascade, activated through the alternative, classical, and lectin-binding pathways, is a crucial component of immunity and inflammation. It contributes to processes like mast cell degranulation, chemotaxis, and cell lysis. Initially, complement was not thought to play a role in the CNS until relationships between complement proteins and glial cells were observed, such as the roles of C3a, C3b, and C5a in the chemotaxis and phagocytic functions of microglia in neuroinflammation [38]. An autoimmune disease, neuromyelitis optica, is an example of complement-induced damage to the CNS. IgG autoantibodies, combined with complement proteins, downregulate aquaporin-4 water channel expression in astrocytes, leading to the breakdown of myelin in the CNS [39]. A recent trial using eculizumab, a C5-inhibiting monoclonal antibody, suggests that targeting the complement system might be effective in reducing neuroinflammation [40]. As with many aspects of innate immunity, the complement cascade is generally considered a double-edged sword within the CNS, exhibiting a protective effect at physiological and acute levels but causing damage when chronically stimulated.
The enzyme cyclooxygenase converts arachidonic acid into eicosanoid groups, such as prostaglandins and thromboxanes, and has various inflammatory functions [41]. The pathways of its two common isoforms, COX-1 and COX-2, are increasingly associated with neuroinflammation and neurodegeneration, with COX inhibitors like non-steroidal anti-inflammatory drugs (NSAIDs) offering therapeutic potential. Both isoforms have distinct roles in normal physiology and pathology (Fig. 1) [14]. COX-1 expression leading to prostaglandin synthesis is observed in microglia [42
