Dynamic programming and memory of monocytes by varying signal strengths of innate stimulants

Abstract

In response to changing external signal strength, innate monocytes may be dynamically programmed into distinct functional states, which may bear significance relevance in host pathophysiology. However, molecular mechanisms that control innate memory dynamics are not well understood nor extensively studied. Using lipopolysaccharide (LPS), the model stimulant of Toll-Like-Receptor 4 (TLR4), we observed that the expressions of pro-inflammatory mediators are preferentially sustained in monocytes adapted by subclinical super-lower dose LPS, and suppressed/tolerized in monocytes programmed by higher dosages of LPS. These phenomena are well conserved in both mice and human monocytes. At the molecular level, we observed that monocytes programmed by super-low dose LPS maintain higher levels of transcription factor IRF5. We also observed that the inflammatory monocyte programming is dependent upon TRAM/TRIF but not MyD88. Similar to LPS, we also observed biphasic inflammatory adaptation and tolerance in monocytes challenged with varying dosages of TLR7 agonist. In sharp contrast, rising doses of TLR3 agonist preferentially caused inflammatory adaptation without inducing tolerance. At the functional level, we observed that in vivo programming of monocytes by subclinical dose LPS exacerbates the progression of atherosclerosis. Taken together, our study provides novel mechanisms for the dynamic programming/memory of innate monocytes and their pathological implications in atherosclerosis.