In the current study, we show for the first time that plasma levels of LPS are elevated in patients with sALS and AD. Plasma LPS levels may also be related to clinical disease status in sALS. Early stage sALS patients had lower levels of plasma LPS than did patients with more advanced disease. Elevated levels of abnormally activated monocyte/macrophages defined by CD14 co-expression of HLA-DR were found in patients with sALS and AD both in the current and in our previous study (Zhang et al., 2005
). Monocyte activation levels in the current study varied directly with plasma LPS levels. Moreover, the levels of plasma LPS were inversely correlated with monocyte IL-10 expression in sALS patients.
Recent studies on immune activation and disease have found that monocyte/macrophage activation in chronic HIV infection/AIDS (Brenchley et al., 2006
) is associated with LPS levels from gut associated microbial translocation. Sources of plasma LPS include, but are not limited to, commensal and pathogenic bacteria, as well as subclinical opportunistic infections. None of our patients had any active infection at the time of the study. It seems that plasma LPS in sALS and AD might also be from gut associated microbial translocation like that observed in the chronic HIV infection (Brenchley et al., 2006
). As a systemic macrophage activator, LPS administration leads to acute neuronal cell death(Cunningham et al., 2005
) and chronic neuroninflammation and progressive neurondegeneration (Qin et al., 2007
). More specific to ALS, the injection of LPS into SOD1(G37R) ALS mice (Nguyen et al., 2004
) caused a dramatic shortening of their lifespan suggesting that LPS-mediated macrophage activation may exacerbate the pathogenesis of ALS in vivo. The current study suggests that circulating LPS, without specifying the source of LPS, may contribute to disease development in sALS.
Whereas LPS induces classical monocyte activation and production of inflammatory mediators, IL-10 is a cytokine with anti-inflammatory properties that may downregulate monocyte activation (de Waal Malefyt et al., 1991
; Ramani et al., 1993
). The expression of this endogenous IL-10 conferred significant protection from the harmful effects of LPS challenge and reduced expression of pro-inflammatory cytokines such as TNF-α, (Gerard et al., 1993
; Marchant et al., 1994
) and regulated leukocyte-endothelial cell interactions, and microvascular permeability (Hickey et al., 1998
). In other experimental systems, IL-10 exhibited protective effects in models of local inflammation including brain or spinal cord injury (Bethea et al., 1999
High LPS levels observed in plasma from patients with advanced sALS were associated with lower circulating monocyte IL-10 expression. It is unlikely that this decreased level of IL-10 was directly related to systemic exposure of monocytes to elevated levels of circulating LPS as AD patients also had high levels of plasma LPS, but no correlation was found with monocyte IL-10 expression. The loss of systemic monocyte IL-10 expression associated with high plasma LPS levels in sALS may be related to disease pathogenesis. It is possible that LPS associated IL-10 reductions may reduce the endogenous anti-inflammatory capability allowing neuroinflammatory disease progression. Accordingly, the balance between pro- and anti-inflammatory TLR4 signaling pathways triggered in response to bacterial products may influence the development of ALS disease. Systemic LPS levels and LPS activated monocyte/macrophage represent two new co-factors that may play significant roles in the pathogenesis of ALS and as such represent novel targets for therapeutic intervention in patients with ALS.