Mevalonate metabolites contribute to granulocyte chemotaxis, cytokine production, and sepsis mortality

Hussain, Jamal

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https://hdl.handle.net/2142/117533 Copy

Description

Title

Mevalonate metabolites contribute to granulocyte chemotaxis, cytokine production, and sepsis mortality

Author(s)

Hussain, Jamal

Issue Date

2022-09-19

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

McKim, Daniel B

Doctoral Committee Chair(s)

Gaskins, Rex H

Committee Member(s)

• Wang, Bo
• Kukekova, Anna V

Department of Study

Food Science & Human Nutrition

Discipline

Food Science & Human Nutrition

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Sepsis
• Statins
• Small GTPases
• Isoprenoids

Abstract

Sepsis is a life-threatening condition caused by severe systemic inflammatory responses to infection that result in multiple organ dysfunction and failure. Statins, a class of medications used to treat hypercholesterolemia, dramatically increased sepsis survival. However, the pro-survival benefits of statins required significant patient pretreatment, and these unfavorable kinetics prevent the clinical utility of statins for treating sepsis. To overcome the poor clinical kinetic profile of statin intervention during sepsis, the pro-survival mechanisms of statins must first be understood. Mirroring clinical observations, chronic but not acute treatment with simvastatin significantly increased survival in a murine endotoxemia model. This was associated with reduced systemic granulocyte chemotaxis that occurred in a cell-intrinsic manner. In vitro modeling showed that statins abolished chemoattractant responses and that this could be reversed by restoring geranylgeranyl pyrophosphate (GGPP) but not farnesyl pyrophosphate (FPP) nor cholesterol. Treatment with prenyltransferase inhibitors showed that chemoattractant responses were dependent on geranylgeranylation. Proteomic quantification of prenylated proteins revealed several geranylgeranylated candidates that may mediate the effect of statins on chemotaxis, including small GTPases RhoA, CDC42, and Rac1 and also G-protein gamma subunits GNG12, 5, and 2. Given the kinetic problems with initiating statin treatment after sepsis onset, prenyltransferases are a promising interventional candidate for sepsis and critical inflammatory illness.

Graduation Semester

2022-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Jamal Hussain

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