Peripheral Monocytes and Intestinal Macrophages during Chronic Inflammation

Abstract

Inflammation is a complex biological response required to maintain homeostasis, but chronic inflammation increases risk of morbidity and mortality. Monocytes and macrophages often contribute to pathology in chronic inflammatory disorders. We hypothesized that chronic inflammation alters peripheral monocyte and intestinal macrophage prevalence, phenotype, and functions. We predicted these effects are modulated by different biological conditions, and they can be mediated by TNF and the intestinal microbiota. In Chapter 3, we investigated peripheral blood immune cell quantities (immunophenotype) under conditions of homeostasis. We observed that the female reproductive cycle did not have a significant effect on immunophenotype, though there were sex differences. In Chapter 4, we examined the relationships between adiposity, chronic inflammation, circulating monocytes, hyperglycemia, and hyperinsulinemia, in male mice. We found that increased circulating Ly6Chigh monocytes correlated with insulin resistance, and that this was mediated by TNF. In Chapter 5, we observed in non-pregnant female mice that there were temporal effects of obesity on peripheral blood immunophenotype, with an increase in Ly6Chigh monocytes. Pregravid obesity altered immunophenotype at mid-pregnancy. In late pregnancy, removal of TNF did not prevent obesity-associated changes to immunophenotype. Excess gestational weight gain also influenced peripheral immunophenotype in lactation. In Chapter 6, we found that obesity altered ileum and colon CD4-TIM4-, CD4+, and CD4+TIM4+ macrophage numbers, phenotype, and cytokine production, in a temporal and tissue-specific manner. Neither peripheral nor intestinal effects of obesity in non-pregnant female mice were mediated by TNF. We identified that there were microbiota-associated and age-associated effects that contributed to changes in colon macrophages between young and old mice. Obesity, excess gestational weight gain, and biological aging had different effects on intestinal macrophage populations. This research provides a better understanding of how peripheral monocytes and intestinal macrophages change in response to inflammation under different biological conditions across the life course.