Central signaling pathways in chemotactic signaling

Krauklis, Steven Alexander

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https://hdl.handle.net/2142/122259 Copy

Description

Title

Central signaling pathways in chemotactic signaling

Author(s)

Krauklis, Steven Alexander

Issue Date

2023-12-01

Director of Research (if dissertation) or Advisor (if thesis)

Steelman, Andrew J

Doctoral Committee Chair(s)

Ridlon, Jason M

Committee Member(s)

• Dilger, Anna C
• Freund, Gregory G

Department of Study

Nutritional Sciences

Discipline

Nutritional Sciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Chemotaxis
• TAK1
• Astrocytes
• Statin
• Prenylation

Abstract

Systemic inflammation can induce behavioral changes including cognitive impairment, anxiety, lethargy, and depression as well as contribute to many neurological disorders and diseases (Dantzer et al, 2008). Upregulation of Tumor Necrosis Factor and Interleukin-1β, specifically, have been shown to promote sickness behaviors, but inhibition of either individually following a peripheral immune challenge is not sufficient to ameliorate all symptomology (Denstaedt et al., 2018; Maes et al., 1998). Transforming growth factor beta associated kinase (Map3k7 or TAK1) is a key mediator of immune signal transduction in multiple tissues and a broadly expressed mediator of cell growth (Dey et al., 2011; Soto-Díaz et al., 2020). These signals attract immune cells to infiltrate Central nervous system parenchyma, which is linked to cognitive impairment (Hsieh et al., 2014; Rajeev et al., 2022). First, the effect of environmental insult on inflammatory signals within the brain was examined. In addition to increased respiratory health risks, fire service workers display increased incidence of mental illnesses including anxiety, depression, and post-traumatic stress symptoms. Self-contained breathing apparatuses (SCBA) are used by fire service workers to diminish exposure to products of combustion. The use of personal protective equipment, including SCBA is often absent in the overhaul environment, where the building is inspected following the extinction of the active blaze. The overhaul group (OH) was compared to the fireground group (FG), which was transported to the site of the exercise and placed in the portion of the structure where fire and overhaul did not occur. Due to the implications of neuroimmune pathways on mental illness, we examine the effects of unprotected exposure to overhaul on transcript expression in the amygdala and hippocampus. Amygdalae and hippocampi were harvested 2 hours after removal from the overhaul environment. Total RNA was extracted and submitted for sequencing with 100nt single-end reads. Surrogate variable analysis identified 5 surrogate variables to remove sources of variation, such as day effect. Compared to FG, OH amygdala displayed transcription changes in 1269 genes (FDR p<0.05) and the hippocampus showed changes in 1412 genes (FDR p<0.05). In the amygdala, 20 of the affected genes are annotated by Gene Ontology for involvement in inflammatory response. Of the affected hippocampus genes, 15 were identified as playing a role in potassium ion transport by Gene Ontology annotation. Potassium ions flux plays a key role in neuronal hyperpolarization and brain-based inflammasome activation. Thus, our findings suggest unprotected overhaul exposure may impact mental health through the modulation of pathways tied to neuroinflammation and excitotoxicity. Next, whether astrocyte TAK1 was involved in promoting sickness behaviors following peripheral cytokine injection was determined. Specifically, Tak1fl/fl and GfapCreERT2:Tak1fl/fl male and female mice aged 5-6 weeks were treated with tamoxifen for 5 days to induce Tak1 deletion. After a two-week washout period, mice were injected with either sterile saline or recombinant cytokines. Home cage locomotion activity was recorded for 24 hours. As with wildtype mice, Tak1fl/fl displayed significantly less movement in the 6 hours following cytokine injection compared to the saline injected groups. Interestingly, deletion of Tak1 in astrocytes ameliorated cytokine induced changes to locomotion, such that changes in their locomotion were only different from the saline injected groups during the first 2 hours. This demonstrates that astrocytes also modulate the neuroinflammatory response and subsequent sickness behavior. Statins are widely used to treat hypercholesterolemia. They function by inhibiting the production of the rate-limiting metabolite mevalonate, not only inhibiting de novo synthesis of cholesterol but also isoprenoids, which are involved in prenylation, the post-translational lipid modification of proteins (Brealy et al, 2021). Therefore, the role of prenylation, the post-translational lipid modification of proteins, on the chemoattractant response to the chemoattractant C5a was investigated. Simvastatin treatment abolished the induction of cytoskeletal remodeling response. The inhibitory effect of simvastatin treatment was unaffected by the addition of either farnesyl pyrophosphate (FPP) or squalene but was reversed by restoring geranylgeranyl pyrophosphate (GGPP). Treatment with prenyltransferase inhibitors showed that the chemoattractant response to C5a was dependent on geranylgeranylation. Broadly expressed central signaling proteins were shown to be targets for prenylation as well as also key mediators of the C5a response. Taken together, these results illustrate some of the roles of central signaling pathways in inflammatory processes. Furthermore, they demonstrate that chemotactic signaling is mediated by both the production of chemoattractant signals as well as the signal transduction of the response to those signals.

Graduation Semester

2023-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Steven Krauklis

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