Browsing by Subject "Innate immunity"

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    The Functional Role of Receptor-Interacting Protein 140 (RIP140) in Innate Immunity and Metabolic Syndrome
    (2016-12) Lin, Yi-Wei
    Metabolic diseases, such as type II diabetes (T2DM), atherosclerosis and other cardiovascular diseases, are prevalent and are important health issues in the modern world. T2DM contributes to the development of various metabolic diseases. Atherosclerosis is one of the major causes leading to multiple cardiovascular diseases. In order to develop therapeutic strategies, understanding the mechanisms of these metabolic diseases is crucial. It is known that the immune system is highly involved in initiation and progression of metabolic diseases. Macrophages are one of the major leukocytes in innate immunity. Macrophages have two major polarized phenotypes: classical/pro-inflammatory (M1) and alternative/anti-inflammatory (M2). It is widely accepted that M1-M2 switch in macrophage population is essential in disease progression or damage recovery; however, the detailed mechanism of macrophage phenotype switch has not been fully elucidated. In addition, the effect of altering the macrophage phenotype on treating metabolic diseases remains uncertain. Receptor-interacting protein 140 (RIP140) is a co-regulator of numerous nuclear receptors and transcription factors. RIP140 is expressed in various cell types including adipocytes, liver, muscle, heart, neurons, and cells in the monocyte–macrophage lineage. Studies showed that RIP140 expression is positively associated with the progression of metabolic disorders such as obesity, insulin resistance, and glucose intolerance. In addition, studies indicate that RIP140 acts as a co-activator of NFκB to promote macrophage M1 activation and pro-inflammatory responses. My studies further build on this knowledge to uncover the role of RIP140 in the metabolic diseases. First, it was found that RIP140 elevates cholesterol content in macrophages by reducing expression of ABC transporters, which are responsible for cholesterol efflux. The elevated cytosolic cholesterol induces foam cell formation and further enhances progression of atherosclerosis. This study indicated that reducing RIP140 levels effectively ameliorates high-cholesteroldiet-induced atherosclerosis. Second, my study found that reducing RIP140 in macrophages leads to macrophage M2 polarization, resulting in adipose tissue remodeling to brown/beige adipose tissue. This further ameliorates high fat diet-induced T2DM associated metabolic disorders. Moreover, later studies address how RIP140 mediates macrophage M2 activation and M1/M2 switch by its cytosolic function in a wound healing animal model. Final study is to identify a beneficial taxonomic repertoire from macrophage specific RIP140 knockdown (MφRIP140KD) mice. Fecal microbiota transplantation (FMT) from HFD-fed MφRIP140KD to wild type (WT) mice acquired the benefits from donors, which is resistant to development of HFD-induced metabolic diseases. Taken together, this thesis studies elucidate novel functions of RIP140 in polarization and inflammatory responses in macrophages, and identify the benefits of reducing RIP140 expression in macrophages. These findings contribute to our understanding of the relationship between immune and metabolic systems as well as provide a therapeutic target of resolving inflammation and preventing/improving metabolic profiles in T2DM, and atherosclerosis.
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    Streptococcus cristatus modulates epithelial innate immune response through regulating nuclear factor-kappa B pathway.
    (2009-12) Zhang, Guizhen
    Streptococci are the dominant oral commensal organisms. They, along with putative periodontal pathogens, normally colonize multiple oral tissue sites. An emerging paradigm indicates that the host can distinguish between pathogenic and nonpathogenic stimuli, and commensal bacteria could modulate expression of host genes to contribute to mucosal tolerance. Here, I hypothesized that an oral commensal Streptococcus cristatus can attenuate epithelial proinflammatory response to Fusobacterium nucleatum via regulation of Toll-Like Receptor (TLR) signaling, as a mechanism for oral mucosal tolerance to polymicrobial infection. I first demonstrated that S. cristatus itself did not provoke IL-8 production in epithelial cells, and it was able to inhibit IL-8 responses to several putative oral pathogens including F. nucleatum. The inhibitory effect of S. cristatus on IL-8 was independent of its viability and its coaggregation with F. nucleatum, was not related to soluble bacterial products, and appeared to require bacterial contact with epithelial cells. Similar effects were seen with several other species of oral streptococci. Next, I performed pathway-specific microarray analysis to specifically monitor host gene modulation by S. cristatus on a broad scale. I found that S. cristatus altered the F. nucleatum–induced expression of a number of proinflammatory cytokine genes. Profiling of TLR signaling related genes revealed that S. cristatus most significantly impacted the downstream pathways, especially NF-κB, rather than altering TLRs and their adaptors and interacting proteins. Lastly, I examined the underlying mechanism(s) involved in the modulating effect of S. cristatus by looking specifically at its impact on the nuclear factor kappaB (NF-κB) pathway under the Toll-like receptor signaling background. I found that the IL-8 suppression by S. cristatus was coincident with the inhibition of NF-κB activation and IκB-α degradation. Pre-incubation with TLR2 and TLR4 antibodies, however, did not affect the epithelial response to either species alone or in combination. I thus conclude that the oral commensal S. cristatus is not only tolerated by the host, but also able to modulate host inflammatory response to pathogenic species through inhibiting IκB-NF-κB signaling module. The anti-inflammatory effect of S. cristatus might represent a regulatory mechanism present at the epithelial surface to tolerate polymicrobial colonization.