Alteration of lysosome fusion and low-grade inflammation mediated by super-low dose endotoxin [Immunology]

January 13th, 2015 by Baker, B., Geng, S., Chen, K., Diao, N., Yuan, R., Xu, X., Dougherty, S., Stephenson, C., Xiong, H., Chu, H. W., Li, L.

Subclinical super-low dose endotoxin lipopolysaccharide (LPS) is a risk factor for the establishment of low-grade inflammation during the pathogenesis and progression of chronic diseases. However, the underlying mechanisms are not well understood. At the cellular level, a disruption of lysosome fusion with endosome or autophagosome may contribute to the potentiation of low-grade inflammation. In this report, we identified that subclinical super-low dose endotoxin lipopolysaccharide (LPS) can potently inhibit the process of endosome acidification and lysosome fusion with endosome or autophagosome in primary macrophages. Super-low dose LPS induces the inhibitory phosphorylation of VPS34, thus leading to the disruption of endosome-lysosome fusion. This effect may depend upon the clearance and relocation of Tollip in macrophages by super-low dose LPS. Consistent with this notion, Tollip deficient macrophages have constitutively elevated levels of VPS34 inhibitory phosphorylation, and constitutive disruption of endosome-lysosome fusion. By employing a skin excision wound-healing model, we observed that Tollip deficient mice have significantly elevated levels of cellular stress and reduced wound repair. Taken together, our current study reveals a novel mechanism responsible for the modulation of endosome-lysosome fusion and low-grade inflammation in innate macrophages.