Distinct surveillance pathway for immunopathology during acute infection via autophagy and SR-BI.
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.
Institut für Laboratoriumsmedizin, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
Susanne
S
Pfeiler
Institut für Laboratoriumsmedizin, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
Avinash B
AB
Khandagale
Centre for Vascular Research, ARC Centre for Excellence in Advanced Molecular Imaging and Australian Centre for Nanomedicine, University of New South Wales, Sydney, New South Wales 2052, Australia.
Astrid
A
Magenau
Institut für Laboratoriumsmedizin, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
Maryana
M
Nichols
Laboratory of Clinical Chemistry and Haematology and Cell Microscopy Center, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
Harry F G
HF
Heijnen
Universitätsklinik Hamburg-Eppendorf, Hamburg, 20246, Germany.
Franz
F
Rinninger
Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
Tilman
T
Ziegler
Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA.
Stephanie
S
Seveau
Max von Pettenkofer-Institut, Ludwig-Maximilians-Universität, Munich, 80336, Germany.
Sören
S
Schubert
Institut für Pharmazeutische Biologie, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
Stefan
S
Zahler
Institut für Systemische Entzündungsforschung, Universität zu Lübeck, Lübeck, 23538, Germany.
Admar
A
Verschoor
Institute of Innate Immunity, University of Bonn, Bonn, 53127, Germany.|Department of Infectious Diseases and Immunology, UMass Medical School, Worcester, MA 01605, USA.|German Center for Neurodegenerative Diseases (DZNE), Bonn, 53127, Germany.
Eicke
E
Latz
Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
Steffen
S
Massberg
Centre for Vascular Research, ARC Centre for Excellence in Advanced Molecular Imaging and Australian Centre for Nanomedicine, University of New South Wales, Sydney, New South Wales 2052, Australia.
Katharina
K
Gaus
Institut für Laboratoriumsmedizin, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
Bernd
B
Engelmann
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D000071186:Beclin-1 / Q000235:genetics / Q000276:immunology; D006056:Golgi Apparatus / Q000235:genetics / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D021962:Membrane Microdomains / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010873:Pinocytosis / Q000235:genetics / Q000276:immunology*; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000276:immunology*; D013158:Splenic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology
D000071186:Beclin-1; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B
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