Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo.
To investigate the respective contributions of TLR versus IL-1R mediated signals in MyD88 dependent control of Mycobacterium tuberculosis, we compared the outcome of M. tuberculosis infection in MyD88, TRIF/MyD88, IL-1R1, and IL-1beta-deficient mice. All four strains displayed acute mortality with highly increased pulmonary bacterial burden suggesting a major role for IL-1beta signaling in determining the MyD88 dependent phenotype. Unexpectedly, the infected MyD88 and TRIF/MyD88-deficient mice, rather than being defective in IL-1beta expression, displayed increased cytokine levels relative to wild-type animals. Similarly, infected mice deficient in caspase-1 and ASC, which have critical functions in inflammasome-mediated IL-1beta maturation, showed unimpaired IL-1beta production and importantly, were considerably less susceptible to infection than IL-1beta deficient mice. Together our findings reveal a major role for IL-1beta in host resistance to M. tuberculosis and indicate that during this infection the cytokine can be generated by a mechanism that does not require TLR signaling or caspase-1.
Mayer-Barber
Katrin D
KD
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Barber
Daniel L
DL
Shenderov
Kevin
K
White
Sandra D
SD
Wilson
Mark S
MS
Cheever
Allen
A
Kugler
David
D
Hieny
Sara
S
Caspar
Patricia
P
Núñez
Gabriel
G
Schlueter
Dirk
D
Flavell
Richard A
RA
Sutterwala
Fayyaz S
FS
Sher
Alan
A
D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D015153:Blotting, Western; D020170:Caspase 1 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
D033942:Adaptor Proteins, Vesicular Transport; D020170:Caspase 1; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C476286:Ticam1 protein, mouse