Reprogramming of inflammatory monocytes by autophagy modulator LiCl

Abstract

Abstract Chronic inflammation is an underlying feature of a variety of highly prevalent diseases such as diabetes, atherosclerosis, inflammatory bowel disease, and cancer. Subclinical endotoxemia has emerged as a common factor correlated with these diseases, potentially contributing to the establishment of chronic inflammation through skewing non-resolving inflammatory monocytes. A better understanding of the underlying mechanisms for the programming of non-resolving inflammatory monocytes may facilitate effective strategies to treat diverse inflammatory diseases. We have observed that subclinical low dose LPS may enable non-resolving inflammatory monocytes through disrupting lysosome fusion and causing accumulation of inflammatory mediators such as p62 and pellino1. Administration of autophagy enhancers such as LiCl can attenuate the effects of low dose LPS, by reducing the levels of pellino1. Together, our data suggest an inhibition of autophagy in response to chronic exposure to subclinical endotoxin. Autophagy is a widely recognized homeostatic cellular process with anti-inflammatory capacity. Further elucidation of the mechanism behind this inhibition may shed light on the link between chronic inflammation and chronic subclinical endotoxin exposure, and provide new avenues for disease treatment.