*4.3. Neuroinflammation Mediated by Microglial Cells*

Microglial cells are widely distributed throughout the region of the brain and spinal cord and are mainly present in the substantia nigra and hippocampus region of the brain. These cells account for 5–20% of the population of all glia cells in the central nervous system and chiefly represent the immune response, as they possess the ability to perform phagocytosis, manifest the secretion of cytotoxic factors, and act like antigen-presenting cells. These cells originate in the primitive yolk sac during hematopoiesis and later rise and migrate to the developing neural tube [108]. These cells comprise the major cellular component of the immune system of the brain. In healthy conditions, microglia cells initiate quick responses to infection and several other stimuli, thereby modulating inflammation and protecting the environment of the brain.

Microglial cells sense different types of stimuli such as bacterial, viral, or fungal infections; antibodies; compliment factors; cytokines; and chemokines that threaten the homeostasis of the CNS and become activated [109]. These cells comprise two main functions: immune defense, by acting as sentinels and detecting the first signs of pathogen invasion and tissue damage; and maintenance by remodeling, repairing, and supporting the tissues of the central nervous system. In response to environmental and toxic factors, microglial cells induce inflammatory and immune responses in the CNS by becoming functionally polarized and expressing specific functioning reactions by activating proinflammatory cytokines and expressing the surface of receptors through the release of numerous soluble factors [110]. The stimulus can polarize microglial cells toward the distinctive functional roles, which causes the expression of different proteins and cytokines.

Activated inflammatory phenotype microglial cells upregulate the release of proinflammatory cytokines such as IL-1β, IL-6, IL-12, IL-23, inducible nitric oxide synthase (iNOS), and tumor necrosis factor (TNF- α), whereas activated anti-inflammatory phenotype microglial cells lead to the upregulation of arginase-1 [111], insulin-like growth factor (IGF-1), mannose receptor (CD206), chitinase 3, and triggering receptor expressed on myeloid cells 2 (TREM2). All of these inflammatory factors contribute to the process of microglial cell activation, which further leads to the production of cytokines and other inflammatory mediators, hence contributing to apoptotic cell death and neurodegeneration.

#### *4.4. Neuroinflammation Mediated by Astrocyte Cells*

These cells are heterogeneous in type and are highly abundant in the CNS [112]. Based on the stage of development, localization, and subtype, the morphology of the

cells can change. For instance, the astrocytes in white matter are fibrous and exhibit long unbranched processes, whereas the astrocytes in grey matter are protoplasmic and possess short branches. These cells act as sensitive markers for the detection of any disease in the neuronal tissue and are responsible for the crucial functioning of the central nervous system [113]. They play a primary role in the transmission of signals in the synapses and control neural circuits. Astrocytes control the CNS environment by maintaining ion homeostasis, blood flow, and pH regulation and controlling oxidative stress. Based on the activities performed by astrocytes, these cells, in combination with microglial cells, act as the main factor in neuroinflammation [114]. In addition, astrocytes rapidly detect damage signals after any injury and undergo changes in their functioning and morphology in response to control and remove brain insults, but if not controlled, the response may have deleterious consequences.

The pathway that leads to the activation of astrocytes is still lucid and several factors that trigger the activation of these cells are involved in the neuropathology of neurodegenerative diseases [104]. It has been demonstrated that in patients with Alzheimer's disease, astrocytes are activated by the presence of amyloid proteins, thereby causing local inflammation. The internal activation of astrocytes causes the transcription of nuclear factor kappa B (NF-ҡB), which further regulates the secretion and adhesion of chemokines and causes the infiltration of lymphocytes in the cerebrospinal fluid, thereby increasing inflammatory reactions and leading to neurodegeneration [115]. Blocking the activity of NF-ҡB protein in astrocytes can significantly reduce neuroinflammation, and it is suggested as a potential therapy for Alzheimer's disease and several other associated neurological disorders.

Figure 5 depicts the exposure to certain environmental toxins, chemicals, or genetic factors that can lead to the activation of anti-myelin T-lymphocytes. These T-lymphocytes, upon activation, initiate immune responses and inflammation as defense factors. Prolonged exposure to these toxins can induce increased production of inflammatory mediators and cytokines and generate hyper-immune response, which causes the infiltration of inflammatory cytokines and lymphocytes into the cerebrospinal fluid and initiates neuroinflammation. Microglial cells (plural: microglia) are the chief neuronal cells responsible for immune responses and inflammation in the central nervous system. Exposure to certain toxicants can induce alterations in healthy microglial cells, leading to their hypertrophy and dystrophy based on the intensity of the stress and thereby causing neuroinflammation and ultimately neurodegradation.
