Dynamic Programming of Innate Immunity in Health and Disease

Yuan, Ruoxi

Dynamic Programming of Innate Immunity in Health and Disease

dc.contributor.author	Yuan, Ruoxi	en
dc.contributor.committeechair	Ahmed, S. Ansar	en
dc.contributor.committeechair	Li, Liwu	en
dc.contributor.committeemember	LeRoith, Tanya	en
dc.contributor.committeemember	Luo, Xin	en
dc.contributor.department	Biomedical and Veterinary Sciences	en
dc.date.accessioned	2018-04-27T06:00:14Z	en
dc.date.available	2018-04-27T06:00:14Z	en
dc.date.issued	2016-11-02	en
dc.description.abstract	Whether innate immune cells may be adapted into potential memory states has becoming an important question in the field of immunity. Although previous conceptual paradigm failed to acknowledge this important question, emerging clinical and basic observations have started to shed intriguing clues to shake the previous dogma regarding innate immunity of being "simple", "raw", "first-line defense with no memory". We have aimed to further address this fundamental issue in this dissertation work, under the close guidance of Dr. Liwu Li. We have chosen to use the model system of Toll-Like-Receptor (TLR) signaling networks within primary monocytes. TLRs play fundamental roles in sensing pathogen-associated molecular patterns (PAMPs) and modulation of innate immunity. Lipopolysaccharide (LPS), an endotoxin found on the cell membrane of gram-negative bacteria, is the ligand of TLR4 and induces a range of inflammatory as well as anti-inflammatory responses. Higher dosages of LPS were known to cause robust yet transient expression of pro-inflammatory mediators. On the other hand, the effects of super-low dose LPS, commonly manifested in humans with adverse health conditions, have been largely ignored in the basic research field. Super-low dose LPS may skew host immune environment into a mild non-resolving pro-inflammatory state, which is a risk factor for inflammatory diseases such as atherosclerosis, compromised wound healing, and elevated risks for sepsis. Our central hypothesize is that monocytes may be adapted by super-low dose LPS into a non-resolving low-grade inflammatory state conducive for the pathogenesis of inflammatory diseases. We have employed both in vitro cell culture system as well as in vivo disease models to test this hypothesis. For the in vitro system, we have cultured primary murine monocytes with increasing signal strength of LPS. Monocyte phenotypes such as the expression of key inflammatory mediators including cytokines, chemokines, and cellular surface markers were studied. Potential molecular and cellular mechanisms were examined. We revealed a novel low-grade inflammatory monocyte phenotype termed ML adapted by super-low dose LPS, mediated through IRF5. For the in vivo system, we have employed both acute and chronic models of inflammation. For the chronic model, we have tested the effects of super-low dose LPS on monocyte polarization in vivo, as well as its contribution to the pathogenesis of atherosclerosis. Furthermore, we have tested the effects of programmed monocytes on wound healing. For the acute model, we have tested the effects of pre-conditioning with super-low dose LPS on the subsequence risks of sepsis elicited by cecal ligation and puncture. We have demonstrated aggravated atherosclerosis, compromised wound healing, and increased sepsis mortality in mice pre-conditioned with super-low dose LPS. Taken together, our findings reveal that monocytes can be differentially programmed into distinct states, depending on the signal strength of LPS. The differential programming and adaptation of monocytes can occur both in vitro and in vivo, and may bear profound pathological consequences.	en
dc.description.degree	Ph. D.	en
dc.format.medium	ETD	en
dc.identifier.other	vt_gsexam:8718	en
dc.identifier.uri	http://hdl.handle.net/10919/82925	en
dc.publisher	Virginia Tech	en
dc.rights	In Copyright	en
dc.rights.uri	http://rightsstatements.org/vocab/InC/1.0/	en
dc.subject	lipopolysaccharide	en
dc.subject	inflammation	en
dc.subject	monocytes	en
dc.subject	atherosclerosis	en
dc.subject	sepsis	en
dc.subject	wound healing.	en
dc.title	Dynamic Programming of Innate Immunity in Health and Disease	en
dc.type	Dissertation	en
thesis.degree.discipline	Biomedical and Veterinary Sciences	en
thesis.degree.grantor	Virginia Polytechnic Institute and State University	en
thesis.degree.level	doctoral	en
thesis.degree.name	Ph. D.	en