Neuroinflammation: Microglial Activation During Sepsis

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Neuroinflammation: Microglial Activation During Sepsis Monique Michels1, Lucinéia G. Danielski1, Felipe Dal-Pizzol2 and Fabrícia Petronilho1,* 1

Laboratory of Clinical and Experimental Pathophysiology, Posgtraduate Program in Health Sciences, University of Southern of Santa Catarina, Tubarão, SC, Brazil 2

Laboratory of Experimental Pathophysiology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina, Criciúma, SC, Brazil Abstract: Neuroinflammation is presented in the acute phase brain damage as well as chronic diseases. Cells that are directly or indirectly involved in immune responses compose the central nervous system (CNS). Microglia are resident cells of the CNS and, as peripheral macrophages, are activated in presence of some cellular insult, producing a large number of cytokines and chemokines in order to remove toxins from the extracellular space. This activation can lead to a breakdown of the blood-brain barrier, production of reactive oxygen species that is involved in the progression of CNS damage as occurs in septic encephalopathy. Given the growing relevance of microglia in the area of neurotoxicology, we describe the role of microglia and the cellular mechanisms that activate these cells during sepsis. Thus, in this review we focused on the relationship between microglia and neuroinflammation associated with sepsis.

Keywords: Blood-brain barrier, CNS, Encephalopathy, Microglia, Neuroinflammation, Sepsis. 1. INTRODUCTION The central nervous system (CNS) has in its composition, cells that are directly or indirectly involved in immune responses. During sepsis development the brain is one of the first organs to be affected leading to neuroinflammation and this is associated with acute brain dysfunction and long-term cognitive deficits [1, 2]. It is convenient to understand that peripheral inflammation is different from neuroinflammation [3], especially due to astrocytes and microglia, which are cells specific from the CNS [1]. Microglia comprise approximately 12% of the total cell population brain and are the second most abundant glial cell types derived from the myeloid line [4]. Microglia are usually in a resting state but can become active after injury or infection [5] operating with a dual role that may be protective or harmful depending on their state of activation [5,6]. In the human CNS, neuroinflammation and microglia activations are associated with injury, trauma, infection, autoimmune disease such as multiple sclerosis, neuropsychiatric disorders and vascular system damage [6]. The activated microglia was first considered a marker of injury and tissue damage [6]. Studies have suggested that neuroinflammatory diseases involve disruption and consequent loss of the selectivity of the blood brain barrier (BBB), leading to neuroinflammation [7]. The disruption of the BBB may be involved in the activation of microglia. This review aims to summarize the physiology of microglia and its involvement in CNS inflammation and

*Address correspondence to this author at the Programa de Pós Graduação em Ciências da Saúde, Universidade do Sul de Santa Catarina, Tubarão, SC, Brazil, Avenida José Acácio Moreira, 787, 88704-900. Tel/Fax: +55-48-36213363; E-mail: [email protected] mailto Received: February 27, 2014

Revised: May 16, 2014

Accepted: May 17, 2014

1567-2026/14 $58.00+.00

neurodegeneration, and systemic inflammatory diseases with emphasis on sepsis. 2. GLIA CELLS Glia cells include microglia, astrocytes and oligodendrocytes [8]. Microglia are macrophage-like resident and immunocompetent cells of the brain [9], and are the first line of defense in response to pathogens and neuronal injury [10]. These cells communicate through different molecules including prostaglandins, inflammatory cytokines, proteases, chemokines, coagulation factors, acute phase reactants, protease inhibitors, free radical generators, anaphylatoxins, integrins, fibrinolytic factors and other unidentified neurotoxins [11]. Subgroups of microglia may present different activities without being morphologically different. In the adult CNS, most of the microglia are regarded to be in the "resting" state, with characteristic branched morphology [12]. Under certain conditions microglia become activated, morphologically indicated by a modification to an amoeboid form [9]. Even though it is provided that substances liberated from neurons can affect microglial activity [13-15], there are few descriptions that indicate constitutive or inducible variety of microglia in CNS regions under normal conditions. The morphology and density of microglia are regionspecific, being more common in the gray area in CNS [16]. This shows that these differences may be associated to functional heterogeneity, but little is known about the nature of this heterogeneity among and within brain regions. However, parenchymal microglia have many branched and are distinct from other microglial cells, presenting “macrophage-like” morphology, such as those found in perivascular sites [17, 18]. The proximity to the vasculature, © 2014 Bentham Science Publishers

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the organization and the biochemical environment could present specific characteristics to microglial cells [19-23]. It is difficult to study about ‘resting’ microglia, therefore, little is known about their function [24]. Resting microglia are not static, dormant cells, but continuously move and monitor the area in where they reside, looking for pathogens and changes in their microenvironment [24]. Both studies using time-lapse imaging in mice in vivo, showed that microglial cell bodies do not move during normal supervision, but the microglial processes expand and retract dynamically and fast [25, 26]. Resting microglia activated fast after insults in changes in the extracellular environment of the injured or diseased brain and suffer morphological alterations from a resting, branched shape to an active amoeboid shape for easy proliferation, migration and phagocytosis [26]. Microglia are known to recognize agents pathogens using evolutionarily conserved pathogen recognition receptors, for example the Toll-like receptors (TLRs) [10,27]. These cells function as antigen presenting cells (APC) and express low level of major histocompatibility complex (MHC-II) in the brain [4]. They are in contact with other cells in the brain, especially astrocytes, establishing cross-talk mediating synergizes responses both in pathological and physiological conditions [4]. It is well known that microglial progenitors are recruited from the periphery upon brain injury [28]. Furthermore, it has also been shown that microglia residing in the brain can self-renew and undergo mitosis to increase their number in an affected area during different insults [29]. Most of this new microglial population was due to the proliferation of a subpopulation of endogenous microglia, and bone marrowderived macrophages which contributed in low number [28]. The CNS of mammals is always an immune preferential place because of the absence of lymphatic drainage and its separation from the blood by the BBB, playing a crucial role in regulating the access of macromolecules and inflammatory cells to the brain. This is secondary to its selective permeability based on the presence of tight junctions between endothelial cells, the lack of formation of pinocytotic vesicles and the envelopment by astrocytes [3032]. Endothelial cell tight junctions limit the paracellular flow of hydrophilic molecules across the blood-brain barrier [33]. The permeability of the BBB is a complex process caused in part by the activation of matrix metalloproteinases (MMPs), which is part of the neuroinflammatory response [34-36]. Pro-inflammatory cytokines, such as Interleucin1 (IL-1) and Tumor Necrosis Factor- (TNF) have been demonstrated to induce the production of MMP-3 and MMP-9 in cultured microglial and astrocytes [36]. MMP-9 aggravates vasogenic edema development by degrading the basal lamina situated between the endothelia and the astrocytic end feet [36]. Following brain injury, bleeding can occur and the permeability of the BBB can be lost, and the infiltration of blood proteins such as thrombin [37] and fibrinogen [38] triggers inflammation. Lymphocytes, macrophages and leukocytes also migrate from the primary lesion place to the surrounding nervous tissue and secrete many chemokines and cytokines, which amplify the damage [39-40]. Due to

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the influence of these factors, oligodendrocyte progenitor cells, microglia and astrocyte are activated and constitute the glial scar around the lesion place [41]. They express and release a variety of bioactive substances, playing a very important role in tissue repairing processes including BBB repair and neuroinflammation [42]. Moreover, several days after injury fibroblasts intrude from the damaged meninges to the lesion place, secrete and proliferate extracellular matrix molecules (ECMs) including fibronectin, laminin and type IV collagen that form the fibrotic scar [41]. Most of all, there is a great rearrangement of the anatomic structure. The BBB appears to be engaged in septic encephalopathy and this has, in part, a relation to MMPs activity [43]. Together, astrocytes are a crucial source of factors that ‘tighten’ the endothelia [32], thus injury to their end feet may further impair BBB function in sepsis. Cerebral blood flow is lowered in sepsis [44,45], but this is unlikely to be enough to cause neural degeneration [46,47]. Nevertheless, inflammatory mediators [48] could gain access to the brain parenchyma in sepsis through the impaired BBB and operate directly in neurons, leading apoptosis. Moreover, neural damage would result from sepsis-damaged astrocytes being incapable of fulfilling their homeostatic function [49]. The concept that controlled microglia/macrophage activation could be convenient for regenerative processes has been well described in the peripheral nervous system (PNS) [50-53]. It has been shown that the poor capacity to regenerate central axons, compared to peripheral axons, correlates to a limited or suppressed post-injury inflammatory response in the central nervous system [54]. In the PNS, certain, microglia/macrophages rapidly infiltrate injured axon and become activated, an event that correlates with the capacity of the PNS to regenerate [51]. Otherwise, in the CNS the non-permissive environment and the presence of a brain-resident inhibitory activity towards microglia are considered to be mainly responsible for inability of lesioned axons to regenerate [55-58]. Therefore, prior exposure of microglia/macrophages PNS nerve tissue, followed by transplantation into the CNS injury is enough to encourage phagocytic activity and promote a certain degree of axon outgrowth [57-60]. Microglia are among the first to respond to brain injury and are first to activate and migrate to the affected place of neural damage where they secrete cytotoxic and cytotrophic immune mediators [61]. The acute neuroinflammatory response is generally beneficial to the CNS, because it tends to minimize the injury and even contributes to the repair of tissue injuries [62-70]. After activating CNS, microglia may act mainly as collectors and transform brain tissue to restoration, and protect the structures and functions of the brain [24]. Local microglia extend their processes to encompass the damaged area [25] and as a result, the damaged cells are engulfed by phagocytosis via microglia, removing any potentially harmful material in the area and protect neighboring cells. So, microglia act as APCs and engulfed this material for invading pathogenic T cells to generate an adaptive immune response [71,72]. Microglia in common with other cells of the myeloid lineage, have the ability to secrete a plurality of immunomodulatory molecules such as chemokines, cytokines, reactive oxygen and nitrogen species and neurotrophins, which communicate signals to circulating

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cells [73]. Thus, in an inflammatory activated microglia modify the responses of supporting cells through the release of a diversity of factors [74]. Moreover, after CNS insult, resident astrocytes extend their processes together with increased glial fibrillary acidic protein (GFAP) immunoreactivity and become hypertrophic [41]. Research suggests that glial across the lesion site progenitors also generate reactive astrocytes [75]. Few days immediately following injury, there observed is a great increase in the numbers of reactive astrocytes across the lesion site but they were absent from the injury core where the BBB was broken-down [41]. 3. MICROGLIA AND REACTIVE OXYGEN SPECIES In the CNS, reactive oxygen species (ROS), including hydrogen peroxide and superoxide, are produced as toxic byproducts during metabolic processes. Under normal conditions, regulated ROS generation plays a crucial role in diverse functions containing, protecting the host (e.g., antibacterial and antiviral antibacterial effects), signal transduction and oxygen sensing [76, 77]. Moreover, alarge production of ROS, such as during exaggerated immune responses, could be toxic to host cells such as neurons in the central nervous system [78, 79]. Oxidative stress occurs when ROS generation and the antioxidant mechanisms are out of balance. In the recent years, a number of researches have been conducted describing oxidative stress in patients with sepsis, with evidence of increased ROS generation and combined oxidative damage, and antioxidant depletion [80-86]. Some of the functions of the microglia depend on the production of cytokines and chemokines [87-90], and the increase in the production of ROS [91]. Microglia is able to phagocyte and this is related to an increased production of reactive radicals that degrade cellular debris and eliminate pathogens [92, 93]. Superoxide is involved in neurodegeneration, microglial activation and cellular redox imbalance [94]. This is supported by studies that indicated the involvement of microglia in promoting death of Purkinje cells by a mechanism dependent on superoxide [95]. Active microglia also contributes in producing oxidants and neuroactive intermediaries that may influence the behavior [96]. As the enabled microglia are suspected to cause or worsen various neurodegenerative diseases, pharmacological strategies to suppress microglial activity are being explored as therapies [96]. Minocycline, for example, is a tetracycline-derived antibiotic that has anti-inflammatory characteristics in the central nervous system that are separate from its antimicrobial activity [97]. Minocycline easily crosses the blood brain barrier and attenuates inflammation associated with microglial activation. Minocycline reduces the deleterious effects of neuroinflammation on neurogenesis, long-term potentiation, and neuronal survival [98-100]. The recent studies indicate that minocycline abrogates factor nuclear kappa B (NF-B) and mitogenactivated protein kinase (MAP-kinase) dependent signaling pathways in microglia cell cultures and primary microglia [101].

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4. MICROGLIAL INVOLVEMENT IN SEPSIS AND DYSFUNCTION OF BLOOD-BRAIN BARRIER Practically, each neurodevelopmental disorder leads to inflammation with activation of resident microglia, followed by an increase in their numbers and change in their phenotype, a phenomenon commonly called ‘‘reactive gliosis’’ [102]. Insults of the central nervous system, including metabolic dysfunction, trauma or infection lead to microglia activation which involves shifts in morphology, surface receptor expression, cell number, increase of cytokines and production of growth factors [103]. In addition, endothelial cell permeability, activation and injury play key roles in the progression of disease including tumor angiogenesis, inflammation and atherosclerosis [104]. Once there are cell necrosis factors, proinflammatory cytokines or lipopolysaccharide (LPS), glia cells are activated quickly [25], and change their morphology [8]. Furthermore, microglia move to the inflammatory area (phenomenon known as chemotaxis), engulf the offensive material (phagocytosis), and secrete proinflammatory factors leading cell proliferation. Microglia not only control infections leading to inflammation or removing cell debris, but also play important role in tissue repair through the secretion of growth factors [12]. Microglia activation is an indicator of brain inflammation [105,106], and has been documented in sepsis [107]. Circulating pro-inflammatory cytokines are major activators of microglia and astrocytes [108,109]. Cytokines, (TNF and IL-1), injure neurons making microglia activated, directly by the cytokines or by indirect mechanisms, which in turn produce pro-inflammatory cytokines, thus starting a vicious circle [110]. Activated glial cells affect neuronal function and contribute to the development of various diseases such as brain ischemia and traumatic brain injury [8]. Glia cells activate the process of clearing bacteria or virus releasing proinflammatory cytokines and neurotrophic factors, and form glial scars [8]. Severe sepsis has been associated with an uncontrolled systemic inflammatory response to infection that is associated with developing organ dysfunction [111]. An essential feature of sepsis is the production of cytokines, chemokines, ROS and nitric oxide (NO) [112]. Cytokines (IL-1 and TNF-) are liberated in large amounts by macrophages, monocytes and others leucocytes in response to gram-negative or gram-positive bacteria and play a key role in the pathogenesis of septic shock [113-116]. Septic encephalopathy is caused by systemic inflammation in the absence of direct brain infection and medically characterized by disorientation, slowing of mental processes, delirium, impaired attention, disorientation and coma. Septic encephalopathy is an important early sign of sepsis and associated with an increased rate of morbidity and mortality [117]. Brain dysfunction is a frequent complication in critically ill patients and is an independent risk factor for poor outcome prognosis and increased mortality [118]. Cytokines play a crucial role in mediating the inflammatory response following infection or a septic traumatic injury [119]. The innate immunity can be easily triggered after LPS, mainly via activation of TLR-4 [120]. Toll-like receptors are

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Table 1. Differences of events that occur in a healthy brain and septic brain in neuroinflammation.

molecules of first line to start the innate immune response. Among the more than ten TLR identified, [121] TLR4 are shown to be expressed on microglia and neuroinflammatory diseases [122]. The activation of TLR-4 leads to a large production of pro-inflammatory cytokines via activation of transcription factors as NF-B [123]. This rapid response provides a friendly ambience for the synthesis and up-regulation of IL-6 and IL-1, that together we contribute to the perpetuation of the inflammatory challenge [119]. The Rapid growth of TNF follows LPS, which is reported after 30 minutes, promotes synthesis of more and others cytokines with initiation of the acute-phase inflammatory response, oxidative stress and chemokine release. Systemic cytokines, including IL-1, can connect receivers and translocate through the intact BBB [124]. Since endothelial cell tight junctions make up the basis of the BBB, damage to these cells would lead to leakage of brain vessels which permitting leakage of potentially toxic serum proteins and blood cells in the CNS [125]. IL-1 can be regarded as the prototypic multifunctional and pleiotropic cytokine due to its generalized effects on immune signaling, CNS functions, and its prominence in several diseases [126, 127]. Pro-inflammatory cytokines, especially TNF- and IL-1, which are generated in the periphery, communicate with the CNS especially by primary autonomic afferents or by the circumventricular region, where the BBB is discontinuous or absent [128]. In this respect, sepsis is associated with increase in the levels of cytokines (IL-1 and TNF- ) in the cerebrospinal fluid (CSF) [129] and brain tissue such as hippocampus and cortex. It is known that the IL-1 pathway regulates hematopoiesis, inflammation, cognition and angiogenesis, [130, 131] and that a sustained systemic inflammation could contribute to prolong or exacerbate brain dysfunction [132, 133, 134]. Semmler et al. demonstrated that in rats a peripheral inflammatory reaction induced by LPS, as a model for sepsis, leads to profound activation of glial cells in the CNS, including microglia [135]. Microglial activation represents

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one of the first shifts observed in sepsis-associated encephalopathy and long microglial activation may affect other CNS cells [118]. Early microglial activation in sepsis was found in mice models within 4 hours following LPS injection, measured by the increased proinflammatory cytokine (IL1 levels) in the microglia [119]. Experimental researchers showed that these proinflammatory mediators liberate in the CNS at the first manifestation of sepsis which in turn leads to neuronal loss within vulnerable areas of the CNS, including the hippocampus [123, 136, 137]. These results showed a neuropathological basis for hippocampal atrophy, lingering cognitive impairment and electroencephalographic changes observed in sepsis survivors [124]. A recent research has detected in aged rats the increased occurrence of the chemokine MIP-1 and IL-1, TNF- and IL-1 and of markers for microglial cells (IBA-1, F4/80, Cd68 and Cd86) and reactive astrocytes (GFAP and Lcn2), where the neurogenesis was strictly diminished in aged brains [138]. Many glial cells are related to inflammatory response in the CNS via various functions such as antigenpresenting capacity, production of proinflammatory cytokines, and maintenance of the BBB [139] (Fig. 1 and Table 1). Sepsis leads to activation of endothelial cells, which results in BBB impairment and penetration of many mediators to the brain. Experimental data showed that earlier after sepsis, endothelial nitric oxide synthase-derived nitric oxide show proinflammatory characteristics, which contributes to the activation and impairment of cerebrovascular endothelial cells [140]. A study suggests that the endothelin (ET) could participate in inflammatory brain diseases [141] and also associated with severity of sepsis/endotoxemia [142, 143] and that blockade of ETB may restore disorder of brain function induced by inflammation [141]. As a plausible scenario of septic encephalopathy development, the following events are thought to occur sequentially: cerebral endothelial activtion starts an inflammatory process by releasing inflammatory mediators or by leading inflammatory mediators to the parenchyma through the impaired BBB, and inflammatory mediators affect cellular metabolism and activity of various types of cells resulting in pathologic abnormalities that range from alterations of neurotransmission to apoptosis [144]. In the sequence of events, activated microglia are hypothesized to play a pivotal role in neuroinflammation leading to delirium [145]. The activated endothelium relays the inflammatory response to the CNS by releasing NO and proinflammatory cytokines that are able to interact with adjacent brain cells. Other after effects of endothelial activation may include microcirculatory dysfunction, which can implicate cerebral perfusion [146]. Endothelial activation changes vascular tone and induces coagulopathy and microcirculatory dysfunctions, which in turn favor ischemic and hemorrhagic lesions [127]. Neuropathological research conducted on nonsurvivors of septic shock suggest that ischemia is consistently observed in CNS areas susceptible to low cerebral flow and that hemorrhages can be found in about 10% of cases [9, 127].

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Fig. (1). Neuroinflammation in sepsis. In sepsis occurs BBB permeability, endothelial activation and release of pro-inflammatory mediators such cytokines, NO, ROS and MMPs with subsequent microglial activation.

For many years glial cells were neglected by scientists as secondary cells in the CNS, being neurons the focus of extensive research. However, more and more glial cells are demonstrating their importance for the adequate function of CNS, both under physiological and pathological situations. Thus, glial cells, mainly the microglia, could be a future therapeutic target in the treatment of both acute and chronic conditions associated with neuroinflammation and brain dysfunctions.

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CONFLICT OF INTEREST

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The authors confirm that this article content has no conflict of interest. [10]

ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2]

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