Recent research indicates crucial roles of autophagy during sepsis. In animal models of sepsis induced by cecal ligation and puncture (CLP) or the systemic administration of lipopolysaccharides (LPS), autophagy is implicated in the activation and/or damage of various cells/organs, such as immune cells, heart, lung, kidney, and liver. Since sepsis is associated with an increased production of pro- as well as anti-inflammatory cytokines, it has long been considered that hypercytokinemia is a fetal immune response leading to multiple organ failure (MOF) and mortality of humans during sepsis. However, a recent paradigm illuminates the crucial roles of mitochondrial dysfunction as well as the perturbation of autophagy in the pathogenesis of sepsis. In the livers of animal models of sepsis, autophagy is involved in the elimination of damaged mitochondria to prevent the generation of mitochondrial ROS and the initiation of the mitochondrial apoptotic pathway. In addition, many reports now indicate that the role of autophagy is not restricted to the elimination of hazardous malfunctioning mitochondria within the cells; autophagy has been shown to be involved in the regulation of inflammasome activation and the release of cytokines as well as other inflammatory substances. In this review, we summarize recent literature describing the versatile role of autophagy and its possible implications in the pathogenesis of sepsis in the liver.

Folding and packing of membrane proteins are highly influenced by the lipidic component of the membrane. Here, we explore how the hydrophobic mismatch (the difference between the hydrophobic span of a transmembrane protein region and the hydrophobic thickness of the lipid membrane around the protein) influences transmembrane helix packing in a cellular environment. Using a ToxRED assay in Escherichia coli and a Bimolecular Fluorescent Complementation approach in human-derived cells complemented by atomistic molecular dynamics simulations we analyzed the dimerization of Glycophorin A derived transmembrane segments. We concluded that, biological membranes can accommodate transmembrane homo-dimers with a wide range of hydrophobic lengths. Hydrophobic mismatch and its effects on dimerization are found to be considerably weaker than those previously observed in model membranes, or under in vitro conditions, indicating that biological membranes (particularly eukaryotic membranes) can adapt to structural deformations through compensatory mechanisms that emerge from their complex structure and composition to alleviate membrane stress. Results based on atomistic simulations support this view, as they revealed that Glycophorin A dimers remain stable, despite of poor hydrophobic match, using mechanisms based on dimer tilting or local membrane thickness perturbations. Furthermore, hetero-dimers with large length disparity between their monomers are also tolerated in cells, and the conclusions that one can draw are essentially similar to those found with homo-dimers. However, large differences between transmembrane helices length hinder the monomer/dimer equilibrium, confirming that, the hydrophobic mismatch has, nonetheless, biologically relevant effects on helix packing in vivo.

The apoptotic death of cells is accompanied by the exposure of “eat-me” signals that serve to prevent necrotic degradation of apoptotic cells, and thereby prevent inflammation, promote resolution of immune responses, and stimulate tissue repair. These “eat-me” signals include the exposure of phosphatidylserine (PS) on the outer plasma membrane during the early stages of apoptosis as well as on the surface of apoptotic bodies, plasma membrane vesicles that are shed during the later stages of cell death. In our recent publication (PLoS Biol. 15(6):e2002711), we describe similar ‘eat-me’ and ‘find-me’ signals present during necroptosis, challenging some of our common assumptions about regulated forms of lytic death.