Dose-dependent effects of endotoxin on monocyte and the underlying mechanisms

Monocytes are dynamic innate immune cells that respond differently based upon the dose and duration of an infection. While super low dose endotoxin is found in chronic inflammatory diseases such as atherosclerosis, exposure to high dose endotoxin leads to sepsis. However, clear characterization of monocytes and the underlying mechanisms in these disease conditions is lacking. To elucidate the missing information, we conducted two different projects. In the first project, we investigated the role of super low dose endotoxin in polarizing monocytes to a prolonged low-grade inflammatory state with no resolution, disrupting homeostasis. This low grade inflammatory phenotype was confirmed by sustained induction of inflammatory mediators CD40 and CD11a. In addition, low grade inflammatory monocytes influence neighboring T cells by suppressing T cell regulatory functions. Mechanistically, we showed that the non-resolving inflammatory phenotypes in monocytes is dependent on non-traditional TLR4 adaptor called TRAM. In the second project, we focused on the effects of high dose endotoxin on monocyte phenotypes. We reported that high dose endotoxin give rise to a mix of both immunosuppressive and pathogenic inflammatory monocytes, leading to monocyte exhaustion. While thorough research is conducted to study the immunosuppressive monocytes and underlying long term effects, role of pathogenic inflammatory monocytes is not well addressed. Monocyte exhaustion leads to elevated levels of CD38, an inflammatory mediator, elevated ROS levels, depleted NAD+ and mitochondrial respiration. STAT1 and KLF4 are critical transcription factors in sustaining exhausted phenotypes. Indeed, TRAM adaptor molecule also mediates this exhaustion as TRAM deletion restores monocyte health. Taken together, our work defines novel monocyte phenotypes and mechanism in super-low dose or high dose endotoxin environments.