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Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 1 Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 1 Microglial Cells Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 Microglial Cells Brianna Cyr Department of Psychology Honors Thesis April 2019 2 Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 Microglial Cells Abstract Microglial cells are responsible for the immune response in the brain. When they come in contact with an entity that requires such a response, the microglia become activated and can phagocytose it. This activated state can potentially lead to neuroinflammation, if sustained for long enough. Neuroinflammation is seen in neurodegenerative diseases such as Parkinson’s Disease and Alzheimer’s Disease. Antioxidants may be able to decrease this inflammation, and an antioxidant of interest is L-carnitine. SIM-A9 microglial cells were activated with LPS and administered L-carnitine. We hypothesize that activated cells rely more on glycolysis than oxidative phosphorylation, ramified cells rely more on oxidative phosphorylation than glycolysis, and the cells that were activated and treated with L-carnitine rely more on oxidative phosphorylation than glycolysis. This study was not able to get usable data in order to conclude if L-carnitine is a potential treatment for neuroinflammation. Further studies need to be conducted to assess the metabolic rates of LPS and L-carnitine treated cells to determine if L-carnitine can be used as a treatment for neuroinflammation. Introduction Microglial cells are one of many types of cells found in the brain that have a number of functions including immune response, phagocytosis, matrix remodeling, and lipid transport. The function most commonly associated with microglia is immune response in the central nervous system. The cells constantly monitor their surrounding environment and can change their morphology depending on the stimuli they Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 3 Microglial Cells encounter (Boche et al., 2013). The two morphologies of interest are the ramified form and the amoeboid form. The ramified form is the typical form microglial cells are found in. The ramified microglia survey the environment with small projections they send out. The amoeboid form is an activated state, these cells lack processes and become phagocytotic. It is thought that when the ramified microglia come across anything that would constitute an immune response, it transforms into the activated amoeboid form seen in Figure 1 (Boche et al., 2013). Figure 1: From Gill et al., 2018. The cycle of ramified microglia transforming into its activated state and back to ramified. It has previously been reported that there are many forms of activated microglia, but the two forms of interest are the M1 and M2 states (Boche et al., 2013 & Orihuela et al., 2015). Generally, M1 is thought of as a pro-inflammatory state whereas M2 is associated with neuroprotection. When a microglial cell is activated to the M1 state, it triggers the activation of mitogen-activated protein kinase (MAPK), causes the 4 Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 Microglial Cells upregulation of inducible nitric oxide synthase, and the secretion of pro-inflammatory cytokines and reactive oxygen species (ROS) (Bhat et al., 1998). The pro- inflammatory cytokines are released by activated microglia, the cytokines can also cause microglia to become activated therefore perpetuating the activation (Orihuela et al., 2015). In contrast, the M2 state is characterized by the expression of heparin- binding lectin, cysteine-rich FIZZ-1, and arginase 1 (Freilich et al., 2013). The M2 phenotype is also thought to help bring the M1 phenotype back to a ramified state (Orihuela et al., 2015). It can release anti-inflammatory factors to resolve inflammation and re-establish homeostasis. In many neurodegenerative diseases an increase in neuroinflammation is observed. This neuroinflammation can be caused by an abundance of activated microglia. The neurodegenerative disease of interest for this study is Parkinson’s Disease (PD). Symptoms of PD include tremors, dystonia, ataxia, and cognitive impairment. In PD, there is chronic inflammation and the release of pro-inflammatory cytokines which causes death of neurons in the substantia nigra pars compacta (Long-Smith et al., 2009). There is ultimately a loss of both acetylcholine and dopamine, both of which help to inhibit tumor necrosis factor alpha and the phosphorylation of MAPKs (Shytle et al., 2004). As mentioned previously, MAPK is activated when microglial cells are in the M1 activated state. Microglia can be activated by administration of many different agents such as complement 3, fractalkine, and phosphatidylserine but lipopolysaccharide (LPS) which is a neurotoxin, is commonly used for this purpose (Nagamoto-Combs et al., 2014, Peña- Ortega, 2017, Orihuela et al., 2015; Gill et al., 2018, Wang et al., 2019). LPS binds to Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 5 Microglial Cells 4 receptors: CD14, scavenger receptor A, Toll-like receptor 4, and complement receptor 3 (Peña-Ortega, 2017). LPS mainly acts on the Toll-like receptor 4 and there is evidence that this receptor is only on microglia or due to the presence of microglia (Peña-Ortega, 2017). This means that the confidence that the activation of microglia is higher than if another agent was used and why LPS was chosen over other agents. Literature has shown that microglial cells that have become activated modify their primary course of producing energy (Wang et al., 2019). Ramified microglia predominantly use oxidative phosphorylation for energy production and activated microglia predominantly use glycolysis. Specifically, there is an increase in the upregulation of the glucose transporter 1 and the glycolytic capacity when microglial cells become activated (Wang et al., 2019). Since neuroinflammation is a factor in the death of neurons, it may be possible to treat this issue by helping the microglia revert back to their ramified state via the use of antioxidants. Antioxidants have been used to decrease neuroinflammation for a variety of diseases (Verlaet et al., 2018; Langley et al., 2017; Yang et al., 2016). Antioxidants scavenge ROS and free radicals. A particular antioxidant of interest is L-carnitine. L- carnitine is a substance that is biosynthesized but also supplemented dietarily (Gulcin, 2005). It plays a role in carrying long chain fatty acids across the mitochondrial membrane for beta-oxidation and then carrying products (such as acetyl-CoA) from beta-oxidation to enter the citric acid cycle. L-carnitine also has a number of antioxidant effects including reducing power, superoxide radical scavenging, hydrogen peroxide scavenging, and metal chelating activities (Gulcin, 2005). In addition, it can prevent free radical formation through inhibition of certain enzymes (Gulcin, 2005). L- 6 Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 Microglial Cells carnitine also has other forms, one of which is acetyl-L-carnitine. This form of carnitine is found primarily in the brain and helps the transfer of acetyl groups for acetylcholine synthesis (Ribas et al., 2013). L-carnitine can convert to this form in the brain through a reversible acetylation reaction. A previous study has shown the effects of direct administration of acetyl-L-carnitine into rats who have been administered LPS to have a positive effect on reducing the number of activated microglia (Kazak & Yarim, 2017). SIM-A9 microglial cells are an immortalized cell line that spontaneously developed from a primary murine culture and behave the same as primary cultured microglia (Nagamoto-Combs et al., 2014). These cells were found to express microglia-specific proteins and variations in morphology, produce cytokines and nitric oxide when stimulated with either LPS or tumor necrosis factor alpha, display phagocytotic activity, express either M1 or M2 phenotypes, and generally retain the microglial characteristics after many passages (Nagamoto-Combs et al., 2014). These characteristics allow us to activate the cells to the M1 state with our chosen agent of LPS, produce its normal factors when in the activated state, and are able to change morphology back to ramified or to the M2 state. These cells are effective in testing our hypothesis and allow us to have a better level of translation as opposed to virally transformed microglia. Our lab previously published a study investigating the effects of LPS and L- carnitine on SIM-A9 cells (Gill et al., 2018). In this past study, SIM-A9 cells were effectively activated (Figure 2) with 2.5 g/mL of LPS and concentrations of 10 and 15 mM of L-carnitine had a significant effect on the cells (Figure 3). Activation was recorded based on nitric oxide production measured by a Greiss analysis. There was Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 7 Microglial Cells a significant difference in nitric oxide production from cells activated with LPS and the cells treated with 10 and 15 mM of L-carnitine. We can infer that L-carnitine played a role in potentially reverting the activated cells back to its ramified form or that it prevents the activation in the first place. The present study aims to take it a step further and try to understand the mechanisms of how the LPS and L-carnitine are affecting the SIM-A9 cells. Figure 2: From Gill et al., 2018. SIM-A9 cells that (A) have been activated with LPS and (B) have not been activated with LPS. 8 Understanding the Metabolic Profile of Lipopolysaccharide Activated SIM-A9 Microglial Cells Figure 3: From Gill et al., 2018. SIM-A9 cells that have been pretreated with (A) 1 mM, (B) 5 mM, (C) 10 mM, and (D) 15 mM L- carnitine for 24 hours before LPS administration. Photos taken 24 hours after LPS administration. In the current study, we aim to investigate the rate of oxygen consumption of ramified microglial cells, activated microglial cells via LPS stimulation, and activated microglial cells via LPS stimulation and L-carnitine treatment.
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