Date of Award

2016

Document Type

Open Access Dissertation

Department

Biomedical Science

Sub-Department

School of Medicine

First Advisor

Prakash Nagarkatti

Second Advisor

Mitzi Nagarkatti

Abstract

Inflammation is implicated in cancer development, degenerative diseases, allergies as well as artherosecelorsis. Dysregulated immune responses lead to chronic inflammation and tissue damage. Finding the ways to terminate inflammatory responses when no longer needed, demands further investigation. Herein, we investigated the modulation of acute and chronic inflammatory disease models by inducing antiinflammatory state. Acute inflammatory model was induced with SEB, an enterotoxin produced by a ubiquitous Gram-positive coccus, Staphylococcus aureus (S. aureus), which exerts profound toxic effects on the immune system, which leads to the cytokine storm and adverse immune response. SEB is the main cause of nosocomial infections, acute and fatal respiratory distress and toxic shock syndrome.

Regulatory T cells (Tregs) are well characterized for their role in maintaining immunological tolerance and immune homeostasis. The immunosuppressive function of T regulatory cells correlates with the expression of the forkhead transcription factor (Foxp3) in these cells. However, the precise regulatory mechanisms which govern the expression of Foxp3 remain unclear. Herein, for the first time, we uncovered the complex interaction of DNA methyltransferase (DNMT) and/or histone deacetylase (HDAC) which leads to the reactivation of transcription of Foxp3 mRNA and induction of Tregs. More specifically, for the first time, we demonstrated the differential regulation of microRNA following administration of an immuno-suppressive environmental contaminant, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in SEB-primed mice. We identified the dual role of miR-31 in induction of Tregs by targeting Foxp3 and CYP-1A.

Because there is a growing incidence of obesity in the last 25 years which defines it as an epidemic condition all over the world, we characterized the mechanism of chronic inflammatory disease in Diet-Induced Obesity (DIO) model. Chronic low-grade, systematic inflammation associated with obesity plays a major role in the development of various chronic disease states, including type 2 diabetes, metabolic syndrome and atherosclerotic cardiovascular disease, which contribute to high rates of mortality and morbidity.

Endocannabinoid system consisting of exogenous and endogenous ligands as well as associated receptors, play a major role in diet intake, energy balance, and regulating of immune functions. In the current study, we offer a better understanding in the underlying mechanism of blockade of cannabinoid CB1 receptor with SR141761A in attenuation of DIO phenotype. We revealed that modulation of neuroimmune guidance cue (Netrin-1) and its related receptor (Unc5b), via blockade of cannabinoid CB1 receptor, leads to less retention of macrophages in adipose tissue, and subsequently causes improvement in metabolic functions. In the current study, we have attempted to investigate the impact of CB1 receptor antagonist, on gut microbial community in DIO phenotype. Herein, for the first time, we identified a rise in Akkermansia muciniphila bacterial community, following blockade of CB1 receptor. Interestingly, we uncovered that therapeutic properties of SR141716A at microbial level can be attributed to the suppression of immunogenic bacteria, Lanchnospiraceace and Erysipelotrichaceae community, in DIO phenotype. Furthermore, we found that SR141716A altered microRNA profile in adipose tissue macrophages and skewed the balance of adipose tissue macrophages to more anti-inflammatory M2 macrophages. These studies provide novel mechanistic information on how microbiota and microRNA can be modulated to suppress acute and chronic inflammation thereby providing new tools to prevent and treat inflammatory diseases.

Share

COinS