Mapping the holonomic signaling network that drives pathological changes in endotoxic shock.

Bacterial lipopolysaccharide (LPS) is among the most potent pathogen-associated molecular patterns (PAMPs). In animals, LPS can induce endotoxic shock, a widely used model of sepsis. Studies of this system have yielded important insights into innate immunity, including key immune sensors and signaling pathways. However, how inflammatory pathways are spatially coordinated across cell types and organs in vivo during endotoxic shock remains poorly understood. Here, we systematically analyzed LPS-induced lethality in mice to define the coordinated contributions of cell death pathways, inflammatory cytokines, and lipid mediators to endotoxic shock pathology. We found that caspase-11 signaling acts primarily in nonhematopoietic cells and drives tissue injury, whereas caspase-8 and RIPK3 function predominantly in hematopoietic cells and are both controlled by TRIF. Although proinflammatory cytokines are thought to promote cell death, it is surprising that cell death and/or components of death signaling are critical for initiating the cytokine storm because disruption of these cell death pathways markedly and preferentially reduces LPS-induced cytokine production in vivo. Combined deficiency of caspase-11, RIPK3, and caspase-8 fully protected mice from LPS-induced death, and additional cyclooxygenase inhibition eliminated remaining sickness behaviors such as reduced mobility. Together, these interventions rendered LPS-treated mice nearly indistinguishable from healthy controls. Overall, we delineate the core of the integrated signaling network that governs the pathological manifestations of LPS-induced endotoxic shock in mice.