Browsing by Subject "macrophage"
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Item Adipose-Derived Stem Cells from Obese Donors Polarize Macrophages and Microglia toward a Pro-Inflammatory Phenotype(MDPI, 2020-12-25) Harrison, Mark A. A.; Wise, Rachel M.; Benjamin, Brooke P.; Hochreiner, Emily M.; Mohiuddin, Omair A.; Bunnell, Bruce A.Macrophages and microglia represent the primary phagocytes and first line of defense in the peripheral and central immune systems. They activate and polarize into a spectrum of pro- and anti-inflammatory phenotypes in response to various stimuli. This activation is tightly regulated to balance the appropriate immune response with tissue repair and homeostasis. Disruption of this balance results in inflammatory disease states and tissue damage. Adipose stem cells (ASCs) have great therapeutic potential because of the potent immunomodulatory capabilities which induce the polarization of microglia and macrophages to the anti-inflammatory, M2, phenotype. In this study, we examined the effects of donor heterogeneity on ASC function. Specifically, we investigated the impact of donor obesity on ASC stemness and immunomodulatory abilities. Our findings revealed that ASCs from obese donors (ObASCs) exhibited reduced stem cell characteristics when compared to ASCs from lean donors (LnASCs). We also found that ObASCs promote a pro-inflammatory phenotype in murine macrophage and microglial cells, as indicated by the upregulated expression of pro-inflammatory genes, increased nitric oxide pathway activity, and impaired phagocytosis and migration. These findings highlight the importance of considering individual donor characteristics such as obesity when selecting donors and cells for use in ASC therapeutic applications and regenerative medicine.Item Chemokine CXCL8 Mediated Intercellular Interactions in HIV-1 associated Dementia(2013-12-01) Mamik, Manmeet K.; Ghorpade, AnujaThis dissertation explores the role of chemokine CXCL8 during human immune deficiency virus (HIV)-1 infection in the brain. Chemokine CXCL8 is an important neutrophil chemoattractant implicated in various neurodegenerative disorders. It is upregulated in the brains and cerebrospinal fluid of HIV-1 infected individuals suggesting its potential role in HIV-1 associated neuroinflammation. Astrocytes are known to be the major contributors to the CXCL8 pool. Interleukin (IL)-1β activated astrocytes exhibit significant upregulation of CXCL8. In order to determine the signaling pathways involved in CXCL8 regulation in astrocytes, we employed pharmacological inhibitors for non-receptor Src homology-2 domain-containing protein tyrosine phosphatase (SHP) 2 and mitogen-activated protein kinases (MAPK) pathway and observed reduced expression of CXCL8 following IL-1β stimulation. Thus, our findings suggest an important role for SHP2 in CXCL8 expression in astrocytes during inflammation, as SHP2, directly or indirectly, modulates p38 and extracellular signal regulated kinase (ERK) MAPK in the signaling cascade leading to CXCL8 production. In the post-antiretroviral therapy (ART) era, low level of productive replication of HIV-1 in brain is a critical component of neuropathogenesis regulation. HIV-1 replication is a complex mechanism involving both host and viral factors. The majority of viral replication in brain occurs in perivascular macrophages and/or 2 microglia. In this study, we investigated the effect of CXCL8 on productive infection of HIV-1 in human monocytes-derived macrophages (MDM) and primary human microglia. The results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2 and induces HIV-1 long terminal repeat (LTR) promoter activity. Detailed understanding of astrocyte signaling and HIV-1 replication, as presented in the thesis, will be relevant to glial-neuronal interactions, which are central to neuroinflammation in HIV-1 and many other neurodegenerative conditions. Also, modulation of levels of CXCL8 can be a therapeutic strategy for control of productive HIV-1 replication in the brain.Item SLEEP APNEA AND ITS ROLE IN OXIDATIVE STRESS AND INFLAMMATION(2014-03) Snyder, Brina; Cunningham, J. Thomas; Cunningham, Rebecca L.Inflammation has been linked with sleep apnea. Sleep apnea is a common comorbidity associated with Parkinson’s disease. Furthermore, both sleep apnea and Parkinson’s disease have been linked with inflammation. A possible mechanism underlying increased inflammation in these disorders is oxidative stress, a hallmark of many neurodegenerative disorders. To examine the role of oxidative stress on inflammation, we used chronic intermittent hypoxia (CIH), an established model for the hypoxemia associated with sleep apnea. CIH consists of recurring events of low oxygen followed by reoxygenation. We hypothesize that CIH causes oxidative stress, which induces inflammation. To test this hypothesis, plasma from adult male rats subjected to 7 days of CIH (3 minute periods of hypoxia (10% oxygen) and 3 minute periods of normoxia (21% oxygen) for 8 hours per day) or normoxia (room air) was tested for AOPP, an indicator of oxidative stress, and circulating inflammatory markers (IL-10, IL-4, IL-6). Our results showed that CIH significantly increased circulating oxidative stress. These results were then correlated with inflammatory markers in the plasma and statistically analyzed for positive associations. IL-6 was found to be significantly increased in CIH, although not associated with oxidative stress. However, CIH did increase IL-4 and IL-10, and these effects were positively associated with circulating oxidative stress. Inflammatory markers IL-4 and IL-6 are generally associated with macrophage-mediated inflammation. Therefore it is possible that CIH-induced oxidative stress underlies macrophage mediated inflammation. These findings suggest that sleep apnea increases oxidative stress and consequently inflammation.Item The Effects of Macrophage Phenotype on Osteogenic Differentiation of MSCs in the Presence of Polyethylene Particles(MDPI, 2021-05-01) Gao, Qi; Rhee, Claire; Maruyama, Masahiro; Li, Zhong Li; Shen, Huaishuang; Zhang, Ning; Utsunomiya, Takeshi; Huang, Elijah Ejun; Yao, Zhenyu; Bunnell, Bruce A.; Lin, Hang; Tuan, Rocky S.; Goodman, Stuart B.Wear debris generated from the bearing surfaces of joint arthroplasties leads to acute and chronic inflammation, which is strongly associated with implant failure. Macrophages derived from monocytes recruited to the local tissues have a significant impact on bone healing and regeneration. Macrophages can adopt various functional phenotypes. While M1 macrophages are pro-inflammatory, M2 macrophages express factors important for tissue repair. Here, we established a 3D co-culture system to investigate how the immune system influences the osteogenic differentiation of mesenchymal stem cells (MSCs) in the presence of micron-sized particles. This system allowed for the simulation of an inflammatory reaction via the addition of Lipopolysaccharide-contaminated polyethylene particles (cPE) and the characterization of bone formation using micro-CT and gene and protein expression. Co-cultures of MSCs with M2 macrophages in the presence of cPE in a 3D environment resulted in the increased expression of osteogenic markers, suggesting facilitation of bone formation. In this model, the upregulation of M2 macrophage expression of immune-associated genes and cytokines contributes to enhanced bone formation by MSCs. This study elucidates how the immune system modulates bone healing in response to an inflammatory stimulus using a unique 3D culture system.