Battle in the Brain - the two Sides of Neuroinflammation

Overview

• Introduction
• Glial cells and macrophages in the first line of defense
• Blood-brain barrier as the brain’s firewall
• Infiltrating peripheral immune cells form the cavalry
• Neuropeptides modulate the battle
• The Three-Act Symphony of Neuroinflammation: Insights from Acute Ischemic Stroke
• Products
• Literature

Introduction

Neuroinflammation, defined as an inflammatory response within the central nervous system (CNS), is a process triggered by different factors, including infection (e.g. COVID-19, toxoplasmosis, malaria), toxic metabolites, trauma, bleeding or autoimmunity processes (Tohidpour et al., 2017). Inflammation in the CNS occurs as a result of cells sensing pathogen-associated molecular patterns (PAMPs, e.g., Lipopolysaccharide (LPS) or lipoteichoic acid (LTA) from bacteria) or damage-associated molecular patterns (DAMPs, e.g., nuclear or cytosolic proteins or nucleic acids from damaged neurons, extracellular ATP or parasite hemozoin) via pattern-recognition receptors (PRRs).
Neuroinflammation is considered neuroprotective in its normally innate response when the inflammatory activity is for a shorter period; however, prolonged or maladaptive neuroinflammation is a key pathological driver of many neurological diseases, including neurodegenerative (e.g., Alzheimer’s and Parkinson’s diseases, epilepsy and motor degenerative disease) and psychiatric diseases (like schizophrenia and depression), as well as stroke, brain cancer, pain syndromes and traumatic brain injury (Chaney et al., 2021). 
Immune activation in the CNS involves microglia and astrocytes, as well as endothelial and perivascular cells. It triggers a transient, self-limiting immune system response and initiates tissue repair. When the normal resolution mechanism fails, persistent inflammatory responses develop that are detrimental and inhibit regeneration. Persistent inflammation can be triggered by endogenous (e.g., genetic mutation, protein aggregates such as α-synuclein or amyloid β) or environmental (e.g., infection, trauma) factors. An unhealthy lifestyle, obesity, diabetes, mental stress, sleep loss and aging also increase the likelihood of neuroinflammation.

Glial cells and macrophages in the first line of defense

Microglia, astrocytes, and oligodendrocytes, the glial cells ubiquitously distributed within the brain parenchyma, together with brain-associated macrophages (BAMs) contribute in a coordinated manner to initiate and modulate the brain's inflammatory response. 
Previously, it was believed that macrophages, microglia, and astrocytes underwent a simplistic polarization into either a pro-inflammatory or anti-inflammatory phenotype. These phenotypes were referred to as M1/M2 for microglia and macrophages (The M1 and M2 Paradigm of Macrophage and Microglia Polarization), or A1/A2 for astrocytes. According to this view, immune cells in the pro-inflammatory phenotype would initiate inflammation by releasing pro-inflammatory cytokines, recruiting other immune cells, and inducing inflammatory responses in neighboring cells. Conversely, cells in the anti-inflammatory phenotype would regulate and potentially halt the inflammatory process by releasing anti-inflammatory cytokines and promoting tissue repair through the release of trophic factors.
However, recent research, especially through genome-wide expression profiling studies, has shed light on the complexity of these cell phenotypes. It has been revealed that these cells can undergo a spectrum of phenotypic states, indicating a more nuanced and finely regulated neuroinflammatory process than previously expected. These new findings challenge the simplistic view of polarization and highlight the multifaceted nature of these cell types during inflammation.

Microglia are the resident innate immune cells of the CNS and account for approximately 10% of the cells in the CNS (Webers et al., 2020) and 20% of the glial cell population of the brain (Troncoso-Escudero et al., 2018). Microglial cells are characterized by highly dynamic processes, which aid in the detection of pathogens and subtle changes in the microenvironment when they are at rest. They act as sentinels that monitor the brain via surface receptors that recognize complement fragments, immunoglobulins, adhesion molecules, chemokine receptors (CCR), toll-like receptors (TLR), purinoreceptors, and scavenger and Fc receptors (Jurga et al., 2020; Prinz et al., 2021; Dermitzakis et al., 2023).
The resting state is transformed into an activated state by danger signals, including PAMPs and DAMPs. Activated microglia communicate by releasing cytokines, which alert surrounding cells and affect their function. They produce both proinflammatory (e.g., tumor necrosis factor-alpha (TNF-α), interleukins IL-1β, IL-6, IL-12, and IL-18, interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS) and monocyte chemotactic protein 1 (MCP-1)), as well as anti-inflammatory mediators (e.g., interleukins IL-4, IL-10 and IL-13, and transforming growth factor-beta (TGF-β)) (Angiulli et al., 2021). Through the release of these cytokines, microglia cells help to recruit other immune cells to the site and initiate the immune defence against pathogens or promote tissue repair.

Remarkably, activation of microglia is accompanied by changes in protein expression. Proteins characteristic of resting microglia, such as P2Y12 (Figure 2), CX3CR1, HexB, or TMEM119, are downregulated, whereas other proteins, such as CD11c (Figure 3), CD86 (Figure 4), CD11b, IBA1, CD68, F4/80 (mouse specific) and Galectin-3 (Figure 5), are upregulated or expressed only upon microglial activation (Benmamar-Badel et al., 2020, Jurga et al., 2020, Almolda et al., 2015, Garcia-Revilla et al., 2022).

In addition to these acute changes, microglia exhibit a long-lasting change after exposure to inflammatory stimuli and become more sensitive to potentially milder stimuli. On the one hand, microglial priming prepares microglia cells for later immune changes; on the other hand, constant exposure of microglia to infections throughout life may contribute to neurodegenerative diseases (Lima et al., 2022). 
Microglial transcriptome changes have been identified in aged brain leading to enhanced inflammation, impaired phagocytosis, and profound morphological changes that reduce immune surveillance. In mouse models of neurodegenerative diseases, microglia cells with a “disease-associated microglial” (DAM) profile have been described (Finger et al., 2022).

Border-associated macrophages (BAMs) are macrophages located in the distinct anatomic specializations of the CNS and peripheral nervous system (PNS) interfaces, particularly in the leptomeninges (pia mater, arachnoid, and dura mater) surrounding the brain and spinal cord, the perivascular plexus, and the choroid plexus. Although classically identified as an integral component of the CNS immune system, the profile of BAMs and their function in maintaining brain defenses and homeostasis are only recently being elucidated using advanced research tools (Mildenberg, 2022).

BAMs originate from a CD206+ macrophage population derived from the early erythro-myeloid progenitors in the yolk sac (being CD206 the unique general marker for BAMs). These cells constitute a stable cell population capable of self-maintenance, and they can even be partially replenished by bone marrow-derived monocytes (at least, at the choroid plexus). On the one hand, the subpopulations of BAMs generally vary in morphology and motility. However, unlike microglia, BAMs do not possess extensive branching processes and display limited motility. On the other hand, like microglia, BAMs possess a high antigen-presenting capacity and can efficiently phagocytose invading pathogens and foreign substances. They secrete cytokines and chemokines that influence the local microenvironment in response to injury or inflammation. Given their location at the border of the CNS/PNS, BAMs play a pivotal role in recruiting circulating immune cells from the periphery. Consequently, they exhibit shared gene upregulation associated with crucial processes like blood vessel development, lipid and cholesterol metabolism, immune response, and antigen presentation. BAMs can be differentiated from microglia by expression of CD206 (Figure 6) and CD163 (Figure 7). Additionally, BAMs express characteristic macrophage markers, including integrin αM (CD11b), IBA1 (Aif1), the receptor for macrophage-colony stimulating factor (Csf1R), and F4/80, reinforcing their macrophage identity (Gerganova, 2022).

Astrocytes constitute ∼50% of all brain cells (Alghamri et al., 2021) and are the most abundant glial cells in the CNS. Astrocytes have multiple functions, including mechanical support of the nervous system, regulation of brain metabolism, uptake and release of neurotransmitters, and participation in the formation of functional synapses, thus helping in the maintenance of a healthy brain (Chiareli et al., 2021).

Under pathological conditions, astrocytes undergo reactive astrogliosis, with morphological and functional changes. Reactive astrocytes are characterized by an increase in glial fibrillary acidic protein (GFAP) and vimentin expression (Singh, 2022) (Figure 8), as well as upregulation of S100B protein synthesis (Higashino et al., 2009). Recent publications describe new promising astrocytic biomarkers in brain injury and neurological diseases, e.g. Aldolase C (ALDOC) (Haddadi et al., 2022), excitatory amino acid transporter 1 (EAAT1, GLAST) (Beschorner et al., 2007) and glutamine synthetase (GS) (Sandhu et al., 2021). Similarly, to microglia, astrocytes become reactive after recognizing signals in their surroundings, such as the accumulation of Aβ aggregates (Chiarini, 2020), and release both pro- or anti-inflammatory cytokines (Tang et al., 2021; Liddelow et al., 2017; Escartin et al., 2021). Astrocytes and microglia play interconnected roles in the inflammatory response within the CNS. Astrocytes can trigger microglia activation by releasing pro-inflammatory cytokines, while activated microglia, in turn, can further stimulate inflammatory responses through cytokine receptors expressed by astrocytes. Reactive astrocytes can also have direct negative effects in the brain. For example, EAAT2, a glutamate importer in astrocytes, is often downregulated in reactive astrocytes which then leads to higher extracellular glutamate concentrations and subsequently endangers neurons via excitotoxicity (Dahlmanns et al, 2023). Consequently, astrocytes exert a modulatory influence on neighboring cells throughout the CNS (Reid and Kuipers, 2021; Rothhammer and Quintana, 2015).

Astrocytes not only control the immune response, but also influence the tissue regeneration process after injury by controlling the process of scar formation as well as neurogenesis and synaptogenesis (Chiareli et al., 2021). Moreover, astrocytes contribute to the integrity and regulation of the blood-brain barrier, which helps to protect the brain from harmful substances. Dysfunctional astrocytes carrying mutations in ubiquitously expressed genes or disease-susceptible polymorphisms can cause or contribute to neurodegenerative disorders such as Huntington’s or Alzheimer’s disease.

Oligodendrocytes are glial cells that initiate myelinization, enable the propagation of electrical potentials, and assist neurons in metabolism. Oligodendrocytes are the main target of the inflammatory response in the CNS, which is triggered by harmful cytokines released by infiltrating macrophages and microglia, cytotoxicity of T lymphocytes, or by antibodies inducing antibody-mediated cytotoxicity (Kölliker-Frers et al., 2021). However, oligodendrocytes also actively influence inflammatory responses by producing a wide range of immunoregulatory factors (e.g., CXCL10, CCL2, CXCR2, CCL3). Oligodendrocytes also express receptors for interleukins (e.g., IL-4, IL-6, IL-10, IL-12) and other cytokines during inflammation and infection, suggesting that they recruit microglia to damaged tissue (Kölliker-Frers et al., 2021). It has been shown that oligodendrocyte progenitor cells (OPCs, also identified as NG2 glia) are not just bystanders in multiple sclerosis, but have the ability to present antigens to T cells and play a much more important role in neuroinflammation and neurodegeneration (Psenicka et al., 2021, Poggi et al., 2023).

Blood-brain-barrier as the brain’s firewall

The Blood-brain barrier (BBB) is the firewall of the brain and as such maintains brain homeostasis and protects neurons. The BBB is a highly specialized, multicellular structure that functions as a selective diffusion barrier between the peripheral circulation and the CNS. The BBB consists of endothelial cells of the capillary wall termed as brain microvascular endothelial cells (BMECs), pericytes, and astrocytes (astroglial basement membranes covered by astrocytic endfeet) (Figure 9). BMECs are connected by complex tight junctions (TJs) and adherent junctions (AJs), e.g., Claudin 5 and Occludin (Figure 10), to restrict the paracellular and transcellular diffusion of molecules in the CNS. The BBB is not a wall in the true sense, but a selective barrier between blood circulation and the brain, that strictly regulates the transfer of various substances and also blood cells from blood to brain. Because the brain is the most energy-consuming organ in the body, various kinds of highly expressed receptors and transporters play a critical role in supplying the brain with essential nutrients, including transferring receptor (TfR), LDL receptor (LDLR) and glucose transporter-1 (GLUT1) (Han and Jiang et al., 2020). Alteration of one property, e.g., transcytosis or transport, can significantly alter the neuronal environment and lead to seizures, autism spectrum, and psychomotor retardation syndromes.

Aging leads to changes in the structure and function of the BBB, which makes the brain more susceptible to neuronal impairment or even neurodegeneration (Hussain et al., 2021). These changes include age-related pericyte dysfunction and vascular cell adhesion molecule 1 (VCAM1) up-regulation. Several studies link for example BBB dysfunction and AD pathology (Profaci et al., 2020). In conditions of stroke, pericytes constrict brain capillaries and then die, which may lead to a long-lasting decrease of blood flow and loss of BBB function, increasing the death of nerve cells. (Hall et al., 2014). Other factors influencing BBB permeability are, e.g., intestinal microbiota changes through unhealthy eating or systemic inflammation (Sun et al., 2022).

Aquaporin-4 (AQP4) is the most abundant bidirectional water channel in the CNS and shows the highest density on perivascular astrocytes endfeet that surround blood vessels. (Figure 11). AQP4 plays a fundamental role in BBB disruption. Abnormal expression and dysfunction of AQP4 has been observed in numerous cognitive disorders, such as AD, vascular dementia and Creutzfeldt-Jakob disease (CJD) (Wang et al., 2022). BBB dysfunction in various brain diseases includes also impaired transport mechanisms. Under physiological conditions, endogenous Aβ is transported bidirectionally across the BBB, with influx receptor RAGE (receptor for advanced glycosylation end products) and efflux receptors LRP1 (low-density lipoprotein receptor-related protein 1) and transporter P-glycoprotein (P-gp) working in tandem. Under AD conditions, increased RAGE and decreased LRP1 and transporter P-gp expression promote Aβ accumulation in the brain. Reduced GLUT1 expression leads to impaired glucose transport and is associated with BBB breakdown in AD pathology. Enhanced transcellular transport is characteristic of the early phase of stroke mediated by increased endothelial caveolin-1 (Cav-1) expression (Han and Jiang, 2020). Through degradation of matrix metalloproteinases (MMPs), extracellular matrix (ECM), and TJ proteins, Cav-1 also directly determines the endothelial barrier integrity following stroke and is responsible to regulate thrombo-inflammatory activity in the peri-infarct area (Zhang et al., 2022).

The integrity of the ECM, and in particular the basement membrane (BM), is essential for the maintenance of proper brain function. In the normal brain, the ECM is composed of chondroitin sulfate proteoglycans (CSPGs), heparan sulphate proteoglycans (HSPGs), hyaluronan, laminins, collagen, and fibronectin, all of which are produced by the cell types found in the brain – neurons, glial cells, and endothelial cells (George et al., 2018). The BM is composed of various ECM molecules, with collagen IV being the most abundant component. The BM forms a thin acellular layer that contributes significantly to vascular barrier function (Xu et al., 2018). Increased expression of ECM components has been described in various brain injuries. For example, the CSPG protein nerve/glial-antigen 2 (NG2), expressed by oligodendrocyte progenitor cells (OPCs), microglial cells, and pericytes, has been found to be increased in glial scars following experimental traumatic brain injury (TBI) (George et al., 2018). High expression of collagen IV and fibronectin has been observed in experimental rodent stroke models and in human stroke tissue (Michalski et al., 2020).

Damage to the BBB allows immune cells or plasma proteins to enter the brain parenchyma, leading to inflammatory processes in the brain. Intercellular adhesion molecule (ICAM) 1, VCAM1 and platelet-endothelial cell adhesion molecule 1 (PECAM 1, CD31) are constitutively expressed at low levels in endothelial cells. Under hypoxic conditions or through cytokine release of IL-1β and TNF-α, ICAM1 and VCAM1 are dramatically increased (Figure 12). ICAM 1 regulates leukocyte recruitment into the brain during neuroinflammation and ischemia, whereas the role of VCAM1 is less clear (Yang et al., 2019). Limiting immune cell trafficking across the BBB has proven to be effective in MS. However, leukocyte trafficking is required at low levels in order to limit infections. The infiltration of immune cells and other substances from the blood enhances the activation of glial cells. Thus, BBB dysfunction enhances the development of neuroinflammation (Takata et al., 2021).

Infiltrating peripheral immune cells form the cavalry

Under normal conditions, the BBB strictly limits the infiltration of peripheral immune cells into the CNS. Only a few subsets of immune cells required for immune surveillance and detected in the cerebrospinal fluid (CSF) migrate through the BBB in a multi-step extravasation process. In the absence of CNS antigens presented by APCs (antigen presenting cells), T cells cross only the endothelium of the BBB but not the glial layer and remain in the CSF. During inflammation, T cells recognize their cognate antigens on perivascular APCs and are reactivated behind the BBB. Matrix metalloproteinases produced by myeloid cells and astrocytes cleave the astrocyte endfeet and allow T cells to enter the CNS parenchyma. Changes in the expression of adhesion molecules and decreased expression of junctional molecules during inflammation facilitate the recruitment of peripheral immune cells across the BBB (Marchetti and Engelhardt, 2020). Peripheral immune cells play a dual role in neuroinflammation and can produce either protective or pathogenic effects (Figure 13).

Neutrophils are the first cells attracted by chemical mediators or DAMPs to the site of injury or infection during the acute phase of CNS pathophysiology. Chil3 (YM-1) is a rodent-specific chitinase-like protein (CLP) expressed by neutrophils (Figure 14), but also alveolar marophages, alternatively activated macrophages and microglia, and osteoclasts (Kang et al., 2022). Release from free oxygen radicals and MMP-9 by neutrophils leads to BBB breakdown and increased infiltration of peripheral immune cells (Manda-Handzlik et al., 2019). Accumulating neutrophils release extracellular web-like structures composed of DNA and proteins called neutrophil extracellular traps (NETs), which protect injured brain from bacterial, parasitic, viral and fungal attack. However, excessive NET formation is implicated in brain disorders and neurological pathologies (Manda-Handzlik et al., 2019).

T cells are important immune cells of the adaptive immune system and are often considered pathogenic when localized to the CNS. There are two main types of T cells: cytotoxic CD8+ cells and CD4+ helper T-cells (Figure 15). Recent studies have shown that T cells play an active role in limiting inflammation and CNS damage. Leptomeningeal macrophages and choroid plexus APCs present antigens to CD4 T cells contained in the CSF under normal conditions, allowing T cells to enter the CNS. In the short term, T cells are neuroprotective but can become pathogenic if the inflammation is not subsided. Pathogenic T cells are described in MS and chronic neurodegenerative diseases like PD or AD. Tissue-resident memory T cells (TRM cells), which are indispensable for local protection against pathogens, have been identified in the parenchyma of mouse and human brains (Smolders et al., 2018). In the healthy brain, CD4 T cells are involved in brain development by helping microglia to mature (Pasciuto et al., 2020).

Monocyte-derived macrophages (MDMs). Classical CCR2-positive monocytes are recruited to the CNS only under pathological conditions, where they differentiate into MDMs. MDMs have higher phagocytic activity than microglia and also have a greater ability to induce antigen-specific T cell proliferation due to higher expression of MHCII (Chang et al., 2021). In stroke, infiltrating macrophages and mononuclear cells are thought to initiate debris clearance and tissue repair in concert with resident cells. Immigration of anti-inflammatory monocytes is associated with improved outcomes after experimental stroke. However acute inflammation can become to chronic, and inflammatory mononuclear cells and macrophages have been found to persist for years in chronic lesions (Spiteri et al., 2022).

Dendritic cells. CD11c-positive brain dendritic cells represent 1 % of immune cells found in the brain and are present in the meninges, choroid plexus, cerebrospinal fluid, and perivascular spaces. They are the predominant antigen-presenting cells of the brain and act as sentinels under steady-state conditions. Their number increases during neuroinflammation. By producing  IFN, dendritic cells can directly target viruses or contribute to neuroinflammation by activating T cells (Constant et al., 2022). Monocyte-derived dendritic cells (moDCs) emerge in the setting of active inflammation and are not present in the healthy parenchymal tissue. In contrast to brain-resident DCs, moDCs are poor APCs and are suggested to play a role in the modulation of the inflammatory milieu and clearance of myelin debris (Giles et al., 2018). 

B cells can be identified by their expression of the B cell lineage-specific antigens CD19 and CD20 and contribute to many aspects of the adaptive immune system, most notably the production and secretion of antibodies. In healthy brains, B cells are rarely found in the CNS parenchyma. More commonly, B cells are found in the meninges, particularly in the dura mater. In viral or bacterial CNS infections, B cells may be recruited and exert a protective function. However, secretion of antibodies can lead to autoimmune CNS diseases (Jain et al., 2021). B cells also play a role in neurodegenerative diseases through antibody-independent mechanisms. It is suggested that B cell-derived cytokines may play a role in the development of MS (Ahn et al., 2021).

Natural Killer (NK) cells. The Innate Lymphoid Cell (ILC) family is a relatively new immune cell population and consists of the three family members ILC1, ILC2 and ILC3. NK cells  are considered part of the ILC1 family. NK cells are bone marrow (BM)-derived haematopoietic cells that are widely distributed in peripheral lymphoid organs and the circulatory system. Under pathological conditions such as stroke, NK cells are recruited by chemokines to the CNS, where they can have a protective function (Wang et al., 2023). However, NK cells may have also pathogenic functions, depending on the NK cell subset, microenvironment, disease type or stage (Liu et al., 2021). Residential NK cells have been identified in the brain parenchyma, that may play a critical role in controlling the extent of CNS inflammation (Hao et al., 2010).

Neuropeptides modulate the battle

Neuropeptides (Neuropeptides) are small endogenous protein messengers synthesized and secreted by neurons that affect development, reproduction, physiology, and behavior (Yeo et al., 2022). However, neuropeptides have been shown to modulate the inflammatory response in the brain by controlling immune cell and glia cell function and BBB permeability (Figure 16). Receptors for several neuropeptides have been detected on microglial cells, such as receptors for NPY (neuropeptide Y), VIP (Vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide). VIP is known to play a critical immunoregulatory role in the periphery and is not only expressed by nerve endings but also by CD4 and CD8 T cells. VIP exhibits anti-inflammatory activity by inhibiting macrophage and microglia activation and acts on mast cells, dendritic cells and synovial fibroblasts. In the brain, VIP promotes neuron proliferation, survival and axon regeneration and is therefore a promising therapeutic target in MS and Parkinson’s disease (Ganea et al., 2015; Martinez et al., 2019). Like VIP, PACAP inhibits inflammation and promotes neuronal survival, and the administration of exogenous PACAP has been shown to be beneficial in a mouse model of T. gondii-induced neuroinflammation (Figueiredo et al., 2022).

Substance P and corticotropin-releasing hormone (CRH) have been shown to activate microglia and mast cells, leading to the release of pro-inflammatory cytokines, which promote permeability of the BBB. By increasing the permeability of BBB, upregulation of substance P, as well as bradykinin and neurotensin, exacerbates stroke pathology (Yeo et al., 2022).
The dysfunction of the neuropeptide activity contributes to several neurological diseases. NPY and substance P have been reported to be reduced in the cerebral cortex of AD patients. Since NPY is reported to attenuate the toxic effects of Aβ accumulation, NPY is discussed as a potential therapeutic option in AD (Yeo et al., 2022). Neuropeptides involved in inflammation also play a central role in the pain response. Migraines and headaches emerge with the vasodilation of blood vessels in the brain following the release of calcitonin gene-related peptide (CGRP) and substance P by afferent nerve terminals (Carr and Frings, 2019).

The Three-Act Symphony of Neuroinflammation: Insights from Acute Ischemic Stroke

An example of the complexity of neuroinflammation involving multiple agents is the inflammatory process after acute ischemic stroke. It has been shown that the inflammatory process after stroke occurs in three stages: acute phase (1): elimination of necrotic cells by microglia and macrophages and initial neutrophil influx in the first minutes to hours,  subacute phase (2) resolution of inflammatory processes by microglial activation and leukocyte infiltration during the first days after the ischemic insult, and late phase (3) astrocytic and microglial reparative processes with contribution of inflammatory cells (Figure 18) (Jurcau and Simion, 2022).

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Literature

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