Abstract
The mechanisms protecting from immunopathology during acute bacterial infections are incompletely known. We found that in response to apoptotic immune cells and live or dead Listeria monocytogenes scavenger receptor BI (SR-BI), an anti-atherogenic lipid exchange mediator, activated internalization mechanisms with characteristics of macropinocytosis and, assisted by Golgi fragmentation, initiated autophagic responses. This was supported by scavenger receptor-induced local increases in membrane cholesterol concentrations which generated lipid domains particularly in cell extensions and the Golgi. SR-BI was a key driver of beclin-1-dependent autophagy during acute bacterial infection of the liver and spleen. Autophagy regulated tissue infiltration of neutrophils, suppressed accumulation of Ly6C+ (inflammatory) macrophages, and prevented hepatocyte necrosis in the core of infectious foci. Perifocal levels of Ly6C+ macrophages and Ly6C− macrophages were unaffected, indicating predominant regulation of the focus core. SR-BI-triggered autophagy promoted co-elimination of apoptotic immune cells and dead bacteria but barely influenced bacterial sequestration and survival or inflammasome activation, thus exclusively counteracting damage inflicted by immune responses. Hence, SR-BI- and autophagy promote a surveillance pathway that partially responds to products of antimicrobial defenses and selectively prevents immunity-induced damage during acute infection. Our findings suggest that control of infection-associated immunopathology can be based on a unified defense operation.
Highlights
The collateral host damage induced by immune responses during infections and sterile injuries represents a major cost of immunity
We show that in host organs infected with Listeria monocytogenes beclin-1-mediated autophagic responses are activated by scavenger receptor BI (SR-BI) to protect organs such as the liver and spleen selectively from the collateral damage induced by antibacterial defenses
Our findings suggest that protection from immunopathology during acute infection can be supported by a unified defense pathway that appears to be based on a distinct pattern of trigger, detector and effector mechanisms and has the characteristics of a bona fide immune process (Fig. 8h)
Summary
The collateral host damage induced by immune responses during infections and sterile injuries represents a major cost of immunity. We show that in host organs infected with Listeria monocytogenes (or Yersinia enterocolitica) beclin-1-mediated autophagic responses are activated by SR-BI to protect organs such as the liver and spleen selectively from the collateral damage induced by antibacterial defenses We identified this scavenger receptor, which promotes lipid exchange between lipoproteins and cells[12,13] and is involved in host cell-pathogen interactions[14,15], as a regulator of lipid domain formation that in turn increased cellular uptake mechanisms with features of macropinocytosis and promoted autophagic flux. Beclin-1-driven autophagy suppressed tissue damage by antimicrobial defenses in infected organs in vivo without affecting sequestration or survival of tissue-associated bacteria It prevented formation of necrotic cells in the core of infectious foci, promoted clearance of apoptotic immune cells, and decreased tissue infiltration and accumulation of neutrophils and inflammatory macrophages. Cooperations between SR-BI and autophagic responses are suggested to promote an independent defense process that can be triggered by products of antimicrobial reactions such as apoptotic immune cells and distinctively controls immunopathology
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