Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice.
Liver X receptors (LXRs) are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. However, exactly how LXRs modulate inflammation during infection remains unknown. To explore this, we used a mouse model of Mycobacterium tuberculosis infection. Upon intratracheal infection with M. tuberculosis, LXRs and LXR target genes were induced in CD11c+ lung and alveolar cells. Furthermore, mice deficient in both LXR isoforms, LXRalpha and LXRbeta (Lxra-/-Lxrb-/- mice), were more susceptible to infection, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. Interestingly, mice solely deficient in LXRalpha, but not those lacking only LXRbeta, mirrored the susceptibility of the Lxra-/-Lxrb-/- animals. Lxra-/-Lxrb-/- mice failed to mount an effective early neutrophilic airway response to infection and showed dysregulation of both pro- and antiinflammatory factors in CD11c+ lung cells. T cell responses were strongly affected in Lxra-/-Lxrb-/- mice, showing near-complete abrogation of the infection-induced Th1 function - and even more so Th17 function - in the lungs. Treatment of WT mice with the LXR agonists TO901317 and GW3965 resulted in a 10-fold decrease of the pulmonary bacterial burden and a comparable increase of Th1/Th17 function in the lungs. The dependence of LXR signaling on the neutrophil IL-17 axis represents what we believe to be a novel function for these nuclear receptors in resistance to M. tuberculosis infection and may provide a new target for therapeutics.
Laboratory of Mycobacterial Immunology, Scientific Institute of Public Health, Brussels, Belgium.
Hannelie
H
Korf
Seppe
S
Vander Beken
Marta
M
Romano
Knut R
KR
Steffensen
Benoît
B
Stijlemans
Jan-Ake
JA
Gustafsson
Johan
J
Grooten
Kris
K
Huygen
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000276:immunology; D007700:Kinetics; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear