Cutting Edge: Caspase-1 Independent IL-1β Production Is Critical for Host Resistance to Mycobacterium tuberculosis and Does Not Require TLR Signaling In Vivo

Abstract

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-1β-deficient mice. All four strains displayed acute mortality with highly increased pulmonary bacterial burden 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 wild-type animals. Similarly, infected mice deficient in caspase-1 and ASC, which have critical functions in inflammasome-mediated IL-1β maturation, showed unimpaired IL-1β production and importantly, were considerably less susceptible to infection than IL-1β deficient mice. Together our findings reveal a major role for IL-1β 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. The Journal of Immunology, 2010, 184: 3326–3330.

Critical role for inflammasome-independent IL-1β production in osteomyelitis

“…Although caspase-1-mediated secretion of IL-1β is the most well characterized mechanism for IL-1β activation, other inflammasomeindependent sources of IL-1β have also been reported to contribute to autoinflammatory disease pathogenesis (10,12). Caspase-1-independent IL-1β has been described to play crucial roles in osteoarthritis (29), particulate-induced lung inflammation (30), host defense against certain pathogens (31,32), and other inflammatory diseases (33). Our findings suggest that PSTPIP2-targeted therapies may prove helpful in the treatment of such diseases.…”

The NLR Adaptor ASC/PYCARD Regulates DUSP10, Mitogen-activated Protein Kinase (MAPK), and Chemokine Induction Independent of the Inflammasome

“…Moreover, a caspase-independent type of necrosis induced by high dose Shigella (Ն50 multiplicity of infection) (16), Neisseria gonorrhoeae (17), or Porphyromonas gingivalis (Pg) (18) is ASC-dependent. Asc Ϫ/Ϫ mice exhibit increased susceptibility to Mycobacterium tuberculosis without reduction in IL-1␤, implying additional ASC function that is distinct from cytokine cleavage (19). Two recent studies of antigen-induced murine arthritis show dependence on Asc but caspase-1, NLRP3, and NLRC4 independence (20,21).…”

Inflammation and Immunopathogenesis of Tuberculosis Progression

“…In mice, targeted mutations of PRR genes impaired host resistance to Mtb (Drennan et al, 2004;Divangahi et al, 2008;Mayer-Barber et al, 2010). Deficiency on PRR adaptor molecules, e.g., MyD88, CARD9, TIR8, resulted in extremely high susceptibility (Garlanda et al, 2007;Dorhoi et al, 210;Mayer-Barber et al, 2010).…”

“…Deficiency on PRR adaptor molecules, e.g., MyD88, CARD9, TIR8, resulted in extremely high susceptibility (Garlanda et al, 2007;Dorhoi et al, 210;Mayer-Barber et al, 2010). Lack of "early response cytokines" (i.e., IL-1, TNF-, IL-6) or their receptors impaired granuloma formation, cytokine and chemokine synthesis and rendered mice extremely susceptible to Mtb infection.…”