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

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Food Science & Human Nutrition

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Hussain, Jamal

Contributors dc:contributor

• McKim, Daniel B
• Gaskins, Rex H
• Wang, Bo
• Kukekova, Anna V

• Sepsis
• Statins
• Small Gtpases
• Isoprenoids

Statement dc:rights

• Copyright 2022 Jamal Hussain

Language dc:language

en, eng

Handle dc:identifier

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

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F117533