The role of peripheral blood dendritic cells and monocytes in the cytokine response to commensal enteric bacteria in HIV-1- infected individuals

Systemic immune activation is a hallmark of pathogenic HIV-1 infection. Microbial translocation, a process in which bacteria and bacterial products move from the lumen of the intestine into the systemic circulation, is increased in HIV-1-infected individuals and is thought to be involved in the development of systemic immune activation. However, the mechanism by which microbial translocation contributes to immune activation is not well characterized. Innate interactions of translocated bacteria with dendritic cells (DCs) or monocytes in the periphery may elicit production of pro-inflammatory cytokines, providing a potential mechanism that contributes to systemic immune activation. However, the response of peripheral DCs and monocytes to commensal enteric bacteria has not been clearly defined.;Therefore, the purpose of these studies was to first characterize the response of peripheral blood DCs and monocytes from healthy donors to whole, commensal, enteric bacteria stimulation in vitro and to then compare the differences in the peripheral APC responses in healthy donors and HIV-1-infected individuals. The data presented here reveal that peripheral DCs and monocytes from healthy donors respond to stimulation with commensal Escherichia coli and Bacteroides fragilis by producing differential levels of both pro- and anti-inflammatory cytokines. E. coli induced a more anti-inflammatory profile dominated by production of IL-10 and B. fragilis induced a more pro-inflammatory IL-23 predominant profile. In HIV-1-infected individuals, significantly more IL-23 was produced in response to E. coli stimulation as compared to uninfected controls. This was likely due to elevated percentages of CD16+ monocytes that had increased expression of Toll-like receptor 4 and lower expression of IL-10 receptor. Both the frequency of CD16+ monocytes and E. coli-induced IL-23 production correlated with plasma levels of soluble CD27, an indicator of systemic immune activation, in HIV-1-infected individuals. This provided a link between bacteria-associated IL-23 production by CD16+ monocytes and a marker of systemic inflammation. These findings contribute significantly to the general understanding of the peripheral APC response to translocated commensal bacteria, and may provide new therapeutic targets that could aid in reducing systemic inflammation due to microbial translocation in the context of HIV-1 infection.