LPS Tolerance inhibits cellular respiration and induces global changes in the secretome

Inflammatory response plays an essential role in the resolution of infections. However, inflammation can be detrimental to the organism and cause irreparable damage, for example during sepsis, when a “cytokine storm” can lead to multiple organ failure and often ends in death. One of the strongest triggers of inflammatory response is bacterial lipopolysaccharide (LPS), acting mostly through Toll-like receptor 4 (TLR4). Prior or prolonged exposure to LPS, however, can induce the state of “endotoxin tolerance” where the macrophages and monocytes do not respond to new endotoxin challenge. The cellular mechanisms regulating this phenomenon remain elusive. Our comprehensive secreted protein analysis comparing LPS-tolerant and -responsive monocyte/macrophage-like cells combined with the extracellular flux analysis reveals the robust switch from the inflammatory to metabolic protein expression as well as points to the involvement of specific proteins that may regulate the change from the responsive to the tolerant state