Date Approved

5-6-2024

Embargo Period

5-6-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Cell Biology and Neuroscience

College

Rowan-Virtua School of Translational Biomedical Engineering & Sciences

Advisor

Jessica Loweth, Ph.D.

Committee Member 1

Kingsley Yin, Ph.D.

Committee Member 2

Bernd Spur, Ph.D.

Committee Member 3

Catherine Neary, Ph.D.

Committee Member 4

Robert Nagele, Ph.D.

Keywords

immunosuppression; macrophages; NF-κB; Pseudomonas aeruginosa; sepsis; THP-1 cells

Subject(s)

Septicemia--Treatment

Disciplines

Cell Biology | Neuroscience and Neurobiology

Abstract

In the late phase of sepsis, immunosuppression occurs, where the host is unable to clear the pre-existing infection and is susceptible to secondary infections. It is believed that the ideal treatments for sepsis should attenuate immunosuppression so that the host can get back to homeostasis. Specialized Pro-resolving Mediators (SPMs) are endogenously- produced fatty acids that resolve infectious inflammation without being immunosuppressive. We hypothesize that an SPM – Resolvin D2 (RvD2) – can augment exhausted macrophage function during the immunosuppressive phase of sepsis. We developed a two-hit model to establish macrophage exhaustion in vitro, and found that RvD2 increased NF-κB activity, TNF-α release, and bacterial clearance in exhausted macrophages compared to controls. Toll-like receptor-2 (TLR2) inhibition abolished RvD2-mediated changes in exhausted macrophages. In a mouse sepsis model, splenic macrophage response to exogenous LPS was reduced compared to controls and was restored by in vivo administration of RvD2. However, if RvD2 was added to monocytes before differentiation to macrophages, RvD2 reduced LPS responses and increased bacterial clearance. The results showed that RvD2 can attenuate macrophage suppression in vitro and in vivo and that this effect was macrophage-specific.

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