Browsing by Subject "Inflammation"
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Item Depression, inflammation, and memory loss among Mexican Americans: analysis of the HABLE cohort(Cambridge University Press, 2017-06-20) Johnson, Leigh A.; Edwards, Melissa; Gamboa, Adriana; Hall, James R.; Robinson, Michelle; O'Bryant, Sid E.Background: This study explored the combined impact of depression and inflammation on memory functioning among Mexican-American adults and elders. Methods: Data were analyzed from 381 participants of the Health and Aging Brain study among Latino Elders (HABLE). Fasting serum samples were collected and assayed in duplicate using electrochemiluminesce on the SECTOR Imager 2400A from Meso Scale Discovery. Positive DepE (depression endophenotype) was codified as any score >1 on a five-point scale based on the GDS-30. Inflammation was determined by TNFɑ levels and categorized by tertiles (1st, 2nd, 3rd). WMS-III LMI and LMII as well as CERAD were utilized as measures of memory. ANOVAs examined group differences between positive DepE and inflammation tertiles with neuropsychological scale scores as outcome variables. Logistic regressions were used to examine level of inflammation and DepE positive status on the risk for MCI. Results: Positive DepE as well as higher inflammation were both independently found to be associated with lower memory scores. Among DepE positive, those who were high in inflammation (3rd tertile) were found to perform significantly worse on WMS-III LM I (F = 4.75, p = 0.003), WMS-III LM II (F = 8.18, p < 0.001), and CERAD List Learning (F = 17.37, p < 0.001) when compared to those low on inflammation (1st tertile). The combination of DepE positive and highest tertile of inflammation was associated with increased risk for MCI diagnosis (OR = 6.06; 95% CI = 3.9-11.2, p < 0.001). Conclusion: Presence of elevated inflammation and positive DepE scores increased risk for worse memory among Mexican-American older adults. Additionally, the combination of DepE and high inflammation was associated with increased risk for MCI diagnosis. This work suggests that depression and inflammation are independently associated with worse memory among Mexican-American adults and elders; however, the combination of both increases risk for poorer memory beyond either alone.Item Dysfunctional neuroimmune pathways promote the development and maintenance of lupus hypertension(2020-05) Pham, Grace S.; Mathis, Keisa W.; Rickards, Caroline A.; Goulopoulou, Styliani; Cunningham, J. Thomas; Ma, Rong; Mathew, Stephen O.Hypertension afflicts nearly half of the adults in the United States and the majority of cases have no known cause. Chronic inflammation has been implicated in the development and maintenance of hypertension, and autoimmunity may comprise one of its sources. Hypertension is highly prevalent in the autoimmune disease systemic lupus erythematosus (SLE), in which chronic aberrant inflammation may be a causative factor. Endogenous neuroimmune pathways, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cholinergic anti-inflammatory pathway, likely contribute to this phenomenon. The HPA axis is a classical neuroimmune mechanism that senses peripheral inflammation via afferent vagal fibers, culminating in the release of the anti-inflammatory hormone cortisol. Previous studies have characterized HPA axis dysfunction in SLE, but less is known about how this dysregulation specifically impacts the hypertension that occurs in the setting of SLE. A second neuroimmune interaction, the cholinergic anti-inflammatory pathway, is an efferent vagus nerve-to-spleen mechanism that relies on T cell-produced acetylcholine to quell inflammation in acute settings and may be hypoactive in chronic inflammatory diseases like SLE. Notably, both of these neuroimmune mechanisms depend on vagus nerve function, identifying the vagus as a potential target for neuromodulation. Furthermore, the relationship between chronic inflammation and hypertension validates the investigation of neuroimmune pathway dysfunction towards novel mechanisms of hypertension. Herewithin, the HPA axis and cholinergic anti-inflammatory pathway are investigated using the well-established NZBWF1 mouse model of lupus hypertension. Our findings are that (1) administration of an inflammatory stimulus that activates vagal afferents elicits comparable neuronal activation in the paraventricular nucleus of the hypothalamus, compared to control mice, despite heightened peripheral inflammation; (2) amplification of efferent vagus nerve activity reduces blood pressure and renal inflammation; and (3) chronic unilateral vagotomy paradoxically results in decreased blood pressure and renal inflammation. Taken together, these findings identify dysfunction in two neuroimmune pathways while demonstrating that interventions targeting these pathways may have therapeutic benefits in lupus hypertension. In terms of future impact, these results may promote continuing inquiry in a more recently discovered neuroimmune pathway (i.e., cholinergic anti-inflammatory pathway), as well as reinstate curiosity in an older, abandoned area of research (i.e., HPA).Item IL-17A ENHANCES DISEASE PATHOLOGY IN BALB/C MICE WHILE CONTRIBUTING TO HOST PROTECTION IN THE C57BL/6 STRAIN DURING INFECTION WITH MYCOPLASMA PULMONIS(2014-03) Mize, Maximillion T.; Simecka, JerryMycoplasma are bacterial organisms that can cause disease within the airways. Specifically, Mycoplasma pneumoniae causes pneumonia in humans which accounts for 30% of all cases of pneumonia worldwide with 100,000 cases per year resulting in hospitalization. This disease is characterized by a persistent infection, often leading to the initiation of chronic inflammation thus damaging the lungs and respiratory tract. In addition, it can also potentiate the disease severity of other respiratory conditions, such as asthma. Infection is often associated with close-quarter communities (i.e. dormitories, military barracks, etc.) allowing for quick spread of the disease. Furthermore, mycoplasma have also been found in livestock demonstrating that this bacteria has infiltrated important aspects of human society. Due to its resistance to antibiotics, such as penicillin, research has been forced to focus on alternative methods to treating disease. Interleukin-17A (IL-17A), a molecule secreted by immune cells, promotes inflammation and has also been implicated in the development of chronic inflammatory conditions. However, the role that IL-17A plays in chronic airway inflammation associated with Mycoplasma infection is currently unknown. Here, we use a mouse model of human pneumonia to determine if IL-17A contributes to tissue damage associated with disease. We demonstrate that targeting IL-17A with antibodies that block its biological function decreases disease severity within a susceptible BALB/c mouse strain. This alleviation was associated with decreased weight loss and lung damage when compared to identical mice not given antibody treatment. However, this method did not decrease bacterial numbers indicating that IL-17A is only associated with inflammation and not clearance of the organism. Interestingly, the opposite affect was seen in the more resistant C57BL/6 mouse strain leading our lab to believe that a genetic predisposition may be the underlying cause of IL-17A associated airway inflammation. A particular genetic background may dictate the amount of IL-17A released during infection, with high amounts predisposing an individual to severe and irreversible tissue damage, thus initiating a state of chronic inflammation. Purpose (a): Mycoplasma cause 30% of all cases of pneumonia worldwide. Infections induce chronic airway inflammation and has also been associated with the exacerbation of other respiratory diseases, like asthma. Due to a prevalence tied to close-quarter communities (dorms, military barracks, etc.), and the possession of a reservoir in livestock, it has infiltrated human society. Furthermore, the lack of a cell wall prevents this organism from being treated with beta-lactam antibiotics forcing research to focus on alternative treatment methods. While Interleukin-17A (IL-17A) has been linked to the induction of chronic inflammatory diseases, its role in mycoplasmosis is currently unknown. Here, we hypothesize that IL-17A leads to chronic inflammation, exacerbating disease pathogenesis. Methods (b): Female BALB/c and C57BL/6 mice, aged 6-12 weeks, were obtained from HARLAN Laboratory, Inc. Mice were housed in sterile microisolator cages supplied with sterile bedding, food, and water all given ad libitum. The UAB CT strain of M. pulmonis was administered intra-nasally to induce infection. Murine anti-IL-17A (αIL-17A) neutralizing antibody was administered intraperitoneal at a concentration 0.150 mg/mL daily. Results were analyzed via one-way and two-way ANOVA. Results (c): After administration of αIL-17A, BALB/c mice infected with M. pulmonis lost less weight when compared to identical mice given Phosphate Buffered Saline (PBS). In addition, infected mice given antibody displayed a reduction in gross lung lesions, however, bacterial burden was not affected. In contrast, infected C57BL/6 mice given αIL-17A antibodies demonstrated increased disease susceptibility associated with an increase in bacterial burden and gross lung lesions when compared to controls given PBS. Conclusions (d): While the presence of αIL-17A in infected BALB/c mice appears to exacerbate disease, this cytokine may play a protective role in C57BL/6 mice infected with the same pathogen. Lung damage decreased, independent of bacterial burden, in infected BALB/c mice administered antibody. This demonstrates that IL-17A does not play a role in pathogen clearance, but does potentiate chronic inflammation. In contrast, infected C57BL/6 mice given antibody had a slight increase in both lung damage and bacterial numbers indicating that IL-17A is needed to decrease disease pathogenesis. Thus, genotypic differences may play a role in how IL-17A influences an immune response through favoring the development of chronic diseases during bacterial infection.Item Interleukin-17A (IL-17A) worsens severe murine respiratory mycoplasma disease(2018-08-01) Mize, Maximillion; Jerry W. Simecka; Rance E. Berg; Harlan P. JonesThe purpose of these studies was to determine the role of Interleukin-17A (IL-17A) in the immune response to respiratory mycoplasma infection. Serum levels of IL-17A increase in disease-susceptible BALB/c mice, but not disease-resistant C57BL/6 mice, infected with Mycoplasma pulmonis. Increased serum IL-17A was associated with mycoplasma pathology during infection in BALB/c mice, including: the presence of pulmonary neutrophils, progressive weight loss, and the development of inflammatory lung lesions. Neutralizing the function of IL-17A using monoclonal anti-IL-17A antibodies during mycoplasma infection reduced disease severity in disease-susceptible BALB/c mice, but not disease-resistant C57BL/6 mice. Providing daily intra-peritoneal injections of anti-IL-17A antibodies to BALB/c mice infected with M. pulmonis was effective at reducing weight loss, the prevalence of clinical signs, and the incidence of gross lesions. Histological lesions, characterized by the presence of pulmonary neutrophils, were also lower in infected BALB/c mice receiving anti-IL-17A antibodies daily. Bacterial burden remained unaffected in mice regardless of treatment. Neutralizing IL-17A throughout infection was effective at reducing late mycoplasma pathology, a period influenced by the actions of adaptive immunity and this is supported by a reduction in disease severity when infected BALB/c mice were provided intra-peritoneal injections of anti-IL-17A antibodies only after T-cells infiltrate the lungs. Pulmonary T-cells, specifically CD4+ T-helper (Th17) cells, were the primary source of IL-17A throughout infection with M. pulmonis in disease-susceptible BALB/c mice. Although Th17 cells increased in the lung after infection, the Th17 response did not reach its peak until the later stages of infection and coincided with when the neutralization of IL-17A started to reduce the severity of disease. IL-17A+ T-cells did not express Retinoic Acid Related (RAR) Orphan Receptor-γt (RORγt), a signature Th17 transcription factor, after infecting BALB/c mice with M. pulmonis and suggests that RORγt is not a suitable marker to identify the IL-17A+ T-cells worsening mycoplasma disease. The effect of neutralizing IL-17A was mimicked in disease-susceptible BALB/c mice depleted of neutrophils during M. pulmonis infection. Depleting neutrophils in BALB/c mice infected with M. pulmonis abrogated weight loss while reducing the appearance of both clinical signs and gross lesions. IL-17A promotes pathology during disease utilizing various mechanisms, one of which is to mobilize and activate neutrophils; however, the IL-17A failed to worsen mycoplasma disease in the absence of neutrophils during M. pulmonis infection in BALB/c mice. These results suggest that IL-17A relies only upon neutrophil recruitment and activation to exacerbate mycoplasma disease. Supporting this, combining the neutralization of IL-17A with the depletion of neutrophils failed to lessen disease severity beyond what either treatment could achieve alone. These findings underscore IL-17A or neutrophils as targets for inhibition to reduce the severity of disease during mycoplasma infection. Both IL-4 and IL-17A increase in the lungs of BALB/c mice infected with M. pulmonis and there are Th17 cells that secrete IL-4. In STAT6 KO mice that respond poorly to IL-4 and generate defective Th2-mediate immunity, neutralizing IL-17A also reduced inflammatory damage during M. pulmonis infection. Treating STAT6 KO mice with anti-IL-17A antibodies during M. pulmonis infection reduced weight loss, the prevalence of clinical signs, and incidence of inflammatory lesions. Like wild-type mice, the pathologic effect of IL-17A manifested during the later stages of M. pulmonis infection in STAT6 KO mice and coincided with the activation of adaptive immunity. Neutralizing IL-17A also failed to change mycoplasma numbers during infection in STAT6 KO mice. IL-17A is highlighted as an independent contributor to mycoplasma pathology with no impact on mycoplasma clearance; inhibiting the activation of Th2- and Th17-mediated immune responses could increase resistance by permitting the development of protective responses during infection. This work emphasizes the importance of IL-17A and Th17 cells as an autonomous immune response worsening neutrophil-mediated pathology during late mycoplasma infection in susceptible mice. Monoclonal antibodies that neutralize the function of IL-17A could reduce the severity of disease during mycoplasma infection in man and animals. Directly targeting neutrophils may also lessen the negative impact IL-17A has on mycoplasma pathology. Vaccines that do not activate IL-17A-mediated immunity could reduce the susceptibility to mycoplasma infection and allow for the development of immune responses that lead to mycoplasma clearance. IL-17A functions to worsen disease severity without impacting mycoplasma clearance, and so IL-17A is identified as a contributor to pathology during infection.Item THE EFFECTS OF ANDROGENS ON CASPASE-1 MEDIATED SIGNALING IN OXIDATIVE STRESSED DOPAMINE NEURONS(2014-03) Holmes, Shaletha S.; Su, Chang; Singh, Meharvan; Cunningham, RebeccaParkinson’s disease (PD), a neurodegenerative disorder characterized by oxidative stress and the loss of dopamine neurons in the midbrain, affects the aging population. In fact, males have a higher risk for PD than females. While the mechanisms remain elusive, one possibility may be that androgens, such as testosterone, play a potential role. Our studies suggest that androgens can increase the expression of Caspase-1, an enzyme whose activity increases with oxidative stress and can result in mitochondrial collapse, ubiquitination, alpha-synuclein–positive lewy body accumulation, inflammation and apoptosis. Therefore, we hypothesize that in oxidative stress conditions, androgens suppress KLF4, a negative regulator of caspase-1, resulting in the increase of Caspase-1 to promote toxic protein accumulation, inflammation, and apoptotic neuronal cell death. This study is related to the role of testosterone in high levels of oxidative stress associated with aging. Purpose (a): Oxidative stress and an extensive loss of dopamine neurons in the nigrostriatal pathway are hallmarks of Parkinson’s disease (PD), a neurodegenerative disorder affecting millions of people. Males have a higher risk for PD than females. While the mechanisms remain elusive, one possibility may be that androgens, such as testosterone, play a potential role. Our studies suggest that androgens can increase the expression of Caspase-1, an enzyme whose activity increases with oxidative stress and can result in mitochondrial collapse, ubiquitination, alpha-synuclein–positive lewy body accumulation, inflammation and apoptosis. We hypothesize that in oxidative stress conditions, androgens suppress KLF4, a negative regulator of caspase-1, resulting in overexpression of Caspase-1 leading to toxic protein accumulation, inflammation, and apoptosis. Methods (b): We exposed a dopaminergic cell line (N27 cells) to a sublethal concentration of the pro-oxidant, tert-butyl hydrogen peroxide (H2O2) for 24 hrs and assessed cell viability in the presence or absence of testosterone. Results (c): Physiologically relevant concentrations of testosterone (0, 1, 10, 100 nM) failed to compromise cell viability in non-oxidatively stressed cells1. In contrast, testosterone did promote cell death in the H2O2 pre-treated cells. In H202 treated cells, testosterone increased caspase-1 expression and activation, as evidenced by an increase in cleaved caspase-1. In addition, KLF4 expression was decreased by testosterone in H2O2 treated cells. The role of KLF4 as a negative regulator of caspase-1 was confirmed in experiments showing that siRNA-mediated knockdown of KLF4 increased caspase-1 levels in H2O2 treated cells. Testosterone increased H202 mediated expression of COX2 signaling, a protein associated with inflammation. Also, testosterone decreased H2O2-induced ubiquitin expression resulting in the accumulation of toxic proteins. Further, testosterone increased H202 induced in apoptosis. Conclusions (d): Overall, these results indicate that androgens such as testosterone exert negative effects under oxidative stress conditions through the suppression of KLF4 and activation of caspase-1 signaling pathways leading to cell death. Thus, supporting a role for androgens for the gender bias observed in PD.