Targeting toll-like receptor 4 related inflammation using small molecule, TAK-242, to attenuate inflammatory damage in pancreatitis and islet transplantation.

Inflammation is usually a carefully controlled process within the body consisting of the pro-inflammatory phase where damaged or infected tissue is removed followed by an anti-inflammatory stage when tissue repair and regeneration takes place. If the pro- or anti-inflammatory stages are not appropriately controlled, the pro-inflammatory process can lead to medical complications caused by excessive damage and the anti-inflammatory process can lead to complications relating to excessive fibrosis. Pancreatitis is a condition where excessive inflammation can result in pancreas and remote organ damage. Excessive inflammation also results in detrimental outcomes in pancreatic islet transplantation which can be utilized to replace beta cell mass lost during type 1 or type 3c diabetes. Toll-like receptor 4, a pattern recognition receptor found on various immune, endothelial, and epithelial cells, can respond to both endogenous and exogenous ligands resulting in enhanced cytokine and chemokine production as well as immune infiltration and activation. In this study, I have used TAK-242, a small molecule inhibitor of TLR4 to analyze the beneficial effects of inhibition of TLR4 in pancreatitis and islet transplantation. In my fist aim I demonstrate the therapeutic potential of inhibition of TLR4 signaling in the context of sterile inflammation using a mouse model of cerulein-induced pancreatitis. In this study I show that administration of TAK-242 prior to cerulein injections results in a less inflammatory environment within the pancreas of mice according to molecular, structural, and flow cytometric analysis. In my next aim I show that targeting TLR4 with TAK-242 can result in enhanced islet transplant outcomes by attenuating innate inflammatory responses immediately after transplantation. In this study, I validate miR-375 and miR-200c as reliable biomarkers for measuring islet graft damage following total pancreatectomy with islet autologous transplantation. I then demonstrate a reduction in these biomarkers and decreases in immune cell activation through inhibition of TLR4. Finally, I show not only does inhibition of TLR4 have effects by directly targeting TLR4 on immune cells, but it also modulates exosome production and cargo of islets in an inflammatory state. These exosomes by themselves have the ability to stimulate macrophage activation which can be subdued by inhibition of TLR4 signaling using TAK-242.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Grantor

Baylor University.

Year dc:date.issued

2024

Author dc:creator

• Mattke, Jordan Dean, 1991-

Advisor dc:contributor.advisor

• Naziruddin, Bashoo.

• Islet transplantation.
• Diabetes.
• Exosomes.
• Pancreas.
• Toll-like receptor 4.
• Pancreatitis.
• Inflammation.

Statement dc:rights

• Baylor University works are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact libraryquestions@baylor.edu for inquiries about permission.

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/2104/13056

OAI identifier oai:identifier

oai:baylor-ir.tdl.org:2104/13056