Date of Award
Doctor of Philosophy (PhD)
Sub-acute/chronic inflammatory diseases are often associated with altered inflammatory response, leading to increased host vulnerability to secondary inflammatory challenges. In the first study, by employing streptozotocin (STZ)-induced diabetes in mice, we further investigate mechanisms leading to enhanced polymorphonuclear leukocytes (PMN) response under hyperglycemia. We show that existence of a proinflammatory state associated with broad increases of macrophages in various organs plays a dominant role in promoting PMN response in diabetic mice. Studies of PMN infiltration during zymosan-induced peritonitis reveal that hyperglycemia enhances PMN recruitment through increasing F4/80+ macrophages in the peritoneal cavity. Insulin reversal of hyperglycemia reduces peritoneal macrophage numbers and ameliorates PMN infiltration. Significantly increased macrophages are also observed in the liver, kidneys, and intestines under hyperglycemia, and are attributable to exacerbated nephropathy and colitis when respective inflammatory conditions are induced. We also find that significant monocytosis of inflammatory F4/80+Gr-1+ monocytes from the spleen and macrophage proliferation in situ synergistically contribute to the increased macrophage population under hyperglycemia. In conclusion, our results demonstrate that STZ-induced hyperglycemic/diabetic mice develop a systemic proinflammatory state mediated by broad infiltration of macrophages. In the second study, we focus on the identification of the carrier that binds to and delivers Shiga toxin 2(Stx2) to the target organ causing hemolytic uremic syndrome (HUS). By employing a murine HUS model through co-injection of LPS-Stx2, we show that, adoptive transfer of CD11b+ leukocytes, but not CD11b- leukocytes, RBC, platelets or plasma, isolated from mice with HUS induces HUS in healthy recipients. Interestingly, we find that LPS priming of mice significantly promotes CD11b+ leukocytes binding to Stx2. Compared to CD11b+ leukocytes from mice without LPS priming, CD11b+ leukocytes isolated from mice after LPS priming demonstrate higher frequencies of toxin binding and augmented potency to induce HUS. In sum, our results demonstrate peripheral CD11b+ myeloid leukocytes act as effective Stx2 carriers that deliver toxin to kidneys causing HUS and that LPS-induced inflammation enhances the carrier capacity and aggravates HUS.
Niu, Shuo, "Regulation Of Innate Immune Cell Response Under Sub-acute/Chronic Inflammatory Conditions." Dissertation, Georgia State University, 2017.