The β2 Integrin Mac-1 Induces Protective LC3-Associated Phagocytosis of Listeria monocytogenes

Alexander Gluschko; Marc Herb; Katja Wiegmann; Oleg Krut; Wolfram F Neiss; Olaf Utermöhlen; Martin Krönke; Michael Schramm

doi:10.1016/j.chom.2018.01.018

The β₂ Integrin Mac-1 Induces Protective LC3-Associated Phagocytosis of Listeria monocytogenes

Cell Host Microbe. 2018 Mar 14;23(3):324-337.e5. doi: 10.1016/j.chom.2018.01.018.

Authors

Alexander Gluschko¹, Marc Herb¹, Katja Wiegmann¹, Oleg Krut², Wolfram F Neiss³, Olaf Utermöhlen⁴, Martin Krönke⁵, Michael Schramm⁶

Affiliations

¹ Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
² Microbiology Department, Paul- Ehrlich-Institut, Langen, Germany.
³ Department of Anatomy I, University of Cologne, Cologne, Germany.
⁴ Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany; Center of Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
⁵ Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany; Center of Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases, (CECAD), University of Cologne, Cologne, Germany; German Center for Infection Research, Cologne, Germany.
⁶ Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany. Electronic address: michael.schramm@uk-koeln.de.

PMID: 29544096
DOI: 10.1016/j.chom.2018.01.018

Abstract

The intracellular pathogen Listeria monocytogenes (L.m.) is targeted by the autophagic machinery, but the molecular mechanisms involved and consequences for anti-listerial immunity remain enigmatic. Here, we demonstrate that L.m. infection of macrophages in vivo exclusively evokes LC3-associated phagocytosis (LAP), but not canonical autophagy, and that targeting of L.m. by LAP is required for anti-listerial immunity. The pathway leading to LAP induction in response to L.m. infection emanates from the β₂ integrin Mac-1 (CR3, integrin α_Mβ₂), a receptor recognizing diverse microbial ligands. Interaction of L.m. with Mac-1 induces acid sphingomyelinase-mediated changes in membrane lipid composition that facilitate assembly and activation of the phagocyte NAPDH oxidase Nox2. Nox2-derived reactive oxygen species then trigger LC3 recruitment to L.m.-containing phagosomes by LAP. By promoting fusion of L.m.-containing phagosomes with lysosomes, LAP increases exposure of L.m. to bactericidal acid hydrolases, thereby enhancing anti-listerial activity of macrophages and immunity of mice.

Keywords: LC3-associated phagocytosis; Listeria monocytogenes; Mac-1/CR3; NAPDH oxidase Nox2; ROS; acid sphingomyelinase; lysosome; macrophages; non-canonical autophagy; β(2) integrin.

MeSH terms

Animals
Autophagy
CD18 Antigens / immunology*
Disease Models, Animal
Host-Pathogen Interactions / immunology*
Listeria monocytogenes / immunology*
Listeria monocytogenes / pathogenicity
Listeriosis / immunology*
Lysosomes
Macrophage-1 Antigen / immunology*
Macrophages / immunology
Mice
Mice, Inbred C57BL
NADPH Oxidase 2 / metabolism
Phagocytosis*
Phagosomes
Reactive Oxygen Species / metabolism
Sphingomyelin Phosphodiesterase
Virulence Factors

Substances

CD18 Antigens
Macrophage-1 Antigen
Reactive Oxygen Species
Virulence Factors
NADPH Oxidase 2
Sphingomyelin Phosphodiesterase