Naturally Occurring Subclinical Endotoxemia in Humans Alters Adaptive and Innate Immune Functions through Reduced MAPK and Increased STAT1 Phosphorylation

Abstract

Multiple studies have shown correlates of immune activation with microbial translocation and plasma LPS during HIV infection. It is unclear whether this activation is due to LPS, residual viral replication, or both. Few studies have addressed the effects of persistent in vivo levels of LPS on specific immune functions in humans in the absence of chronic viral infection or pathological settings such as sepsis. We previously reported on a cohort of HIV negative men with subclinical endotoxemia linked to alterations in CD4/CD8 T cell ratio and plasma cytokine levels. This HIV negative cohort allowed us to assess cellular immune functions in the context of different subclinical plasma LPS levels ex vivo without confounding viral effects. By comparing 2 samples of differing plasma LPS levels from each individual, we now show that subclinical levels of plasma LPS in vivo significantly alter T cell proliferative capacity, monocyte cytokine release and HLA-DR expression, and induce TLR cross-tolerance by decreased phosphorylation of MAPK pathway components. Using this human in vivo model of subclinical endotoxemia, we furthermore show that plasma LPS leads to constitutive activation of STAT1 through autocrine cytokine signaling, suggesting that subclinical endotoxemia in healthy individuals might lead to significant changes in immune function that have thus far not been appreciated.

Proteolytic inactivation of nuclear alarmin high-mobility group box 1 by complement protease C1s during apoptosis

“…Subclinical levels of plasma LPS exists and appears to induce tolerogenic status. 45 Apoptotic HMGB1 could prime this status into a pro-inflammatory state.…”

“…Subclinical levels of LPS are commonly detected in the plasma especially in chronic diseases 54 which can suppress T cell proliferation and retard monocyte response to further challenges with TLR ligands including LPS. 45 A surge of HMGB1 could render otherwise subclinical levels of LPS inflammatory and injurious and C1s might have a role in regulating this.…”

T-cell phenotypes are associated with serum IgE levels in Amish and Hutterite children

“…Although the function of these cells is not known, they express markers consistent with an exhausted type of CD8 T cells. 28,29 Monocytes from Amish children had low expression of HLA-DR, 2 which has been associated with repeated endotoxin exposure 30 and chronic infections 31,32 in other studies. These HLA-DR-low monocytes expressed high levels of 2 inhibitory receptors, ILT3 and ILT5 (Fig 3).…”

B cell responses in older adults with latent tuberculosis: Considerations for vaccine development

“…LPS/endotoxin levels in the bloodstream may also serve as a measure for subclinical infection [ 31 ]. Plasma endotoxin levels were similarly low in both groups ( Figure 1C ).…”