Caspase-1 independent IL-1β Production is critical for MyD88-mediated host resistance to Mycobacterium tuberculosis (42.13)

Abstract

Abstract Host resistance to Mycobacterium tuberculosis (Mtb) requires the TLR/IL-1R adaptor MyD88. To investigate the contributions of TLR versus IL-1R mediated signals in MyD88 dependent control of Mtb, we compared the outcome of Mtb infection in MyD88, TRIF/MyD88, IL-1R1 and IL-1β-deficient mice. All four strains displayed acute mortality with highly increased pulmonary bacterial burdens and necrotic lung pathology suggesting a major role for IL-1β signaling in determining the MyD88 dependent phenotype. Unexpectedly, the infected MyD88 and TRIF/MyD88-deficient mice, rather than being defective in IL-1β expression, displayed increased cytokine levels relative to WT animals, arguing that MyD88 regulates host resistance to Mtb at the level of IL-1β/IL-1R1 signaling rather than TLR-mediated triggering of cytokine production. Similarly, infected mice deficient in caspase-1 and ASC, which have critical functions in inflammasome mediated IL-1β processing, showed unimpaired IL-1β production and importantly, were considerably less susceptible to infection than IL-1β deficient mice. Thus, our data argue that the production of mature host-protective IL-1β during Mtb infection can occur independently of caspase-1 activation and ASC-containing inflammasomes. Together our findings reveal a critical role for IL-1β in acute host resistance to Mtb and indicate that during this bacterial infection the cytokine can be generated by a mechanism that does not require TLR signaling or caspase-1 cleavage.