Autophagy suppresses host adaptive immune responses toward Borrelia burgdorferi.
We have previously demonstrated that inhibition of autophagy increased the Borrelia burgdorferi induced innate cytokine production in vitro, but little is known regarding the effect of autophagy on in vivo models of Borrelia infection. Here, we showed that ATG7-deficient mice that were intra-articular injected with Borrelia spirochetes displayed increased joint swelling, cell influx, and enhanced interleukin-1β and interleukin-6 production by inflamed synovial tissue. Because both interleukin-1β and interleukin-6 are linked to the development of adaptive immune responses, we examine the function of autophagy on Borrelia induced adaptive immunity. Human peripheral blood mononuclear cells treated with autophagy inhibitors showed an increase in interleukin-17, interleukin-22, and interferon-γ production in response to exposure to Borrelia burgdorferi. Increased IL-17 production was dependent on IL-1β release but, interestingly, not on interleukin-23 production. In addition, cytokine quantitative trait loci in ATG9B modulate the Borrelia induced interleukin-17 production. Because high levels of IL-17 have been found in patients with confirmed, severe, chronic borreliosis, we propose that the modulation of autophagy may be a potential target for anti-inflammatory therapy in patients with persistent Lyme disease.
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands;
Kathrin
K
Buffen
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands;
Marije
M
Oosting
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands; and.
Yang
Y
Li
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Thirumala-Devi
TD
Kanneganti
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands;
Mihai G
MG
Netea
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands; leo.joosten@radboudumc.nl.
Leo A B
LA
Joosten
D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D000071193:Autophagy-Related Protein 7 / Q000502:physiology*; D025065:Borrelia burgdorferi / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008193:Lyme Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000097043:Interleukin-22
D000071193:Autophagy-Related Protein 7; D016207:Cytokines; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22; C502661:Atg7 protein, mouse
IL-17; IL-23; Lyme disease