Toll-like receptor 5 (TLR5), IL-1β secretion, and asparagine endopeptidase are critical factors for alveolar macrophage phagocytosis and bacterial killing.

Delphyne Descamps (1) , Le Gars Mathieu (1, 2) , Viviane Balloy (1) , Barbier Diane (1) , Maschalidi Sophia (3) , Tohme Mira (3, 4) , Michel Chignard (1) , Reuben Ramphal (1, 5) , Manoury Bénédicte (3) , Jean-Michel Sallenave (1, 2)

1 Défense innée et inflammation
2 Cellule Pasteur UPMC
3 Tolérance immunitaire et présentation antigénique: impact en auto-immunité et en transplantation
4 U932 - Immunité et cancer
5 UF|Medicine - Department of Medicine [Gainesville]

A deficit in early clearance of Pseudomonas aeruginosa (P. aeruginosa) is crucial in nosocomial pneumonia and in chronic lung infections. Few studies have addressed the role of Toll-like receptors (TLRs), which are early pathogen associated molecular pattern receptors, in pathogen uptake and clearance by alveolar macrophages (AMs). Here, we report that TLR5 engagement is crucial for bacterial clearance by AMs in vitro and in vivo because unflagellated P. aeruginosa or different mutants defective in TLR5 activation were resistant to AM phagocytosis and killing. In addition, the clearance of PAK (a wild-type P. aeruginosa strain) by primary AMs was causally associated with increased IL-1β release, which was dramatically reduced with PAK mutants or in WT PAK-infected primary TLR5(-/-) AMs, demonstrating the dependence of IL-1β production on TLR5. We showed that this IL-1β production was important in endosomal pH acidification and in inducing the killing of bacteria by AMs through asparagine endopeptidase (AEP), a key endosomal cysteine protease. In agreement, AMs from IL-1R1(-/-) and AEP(-/-) mice were unable to kill P. aeruginosa. Altogether, these findings demonstrate that TLR5 engagement plays a major role in P. aeruginosa internalization and in triggering IL-1β formation.

Keywords: alveolar macrophage; Pseudomonas aeruginosa; flagellin; immunity; inflammation; IL-1B; inflammasome; phagocytosis; proteases

Domains: Immunology

Delphyne Descamps, Le Gars Mathieu, Viviane Balloy, Barbier Diane, Maschalidi Sophia, et al.. Toll-like receptor 5 (TLR5), IL-1β secretion, and asparagine endopeptidase are critical factors for alveolar macrophage phagocytosis and bacterial killing.. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (5), pp.1619-24. ⟨10.1073/pnas.1108464109⟩. ⟨pasteur-00667246⟩