Interleukin‐1 Signaling Is Essential for Host Defense during Murine Pulmonary Tuberculosis

Abstract

Interleukin (IL)-1 signaling is required for the containment of infections with intracellular microorganisms, such as Listeria monocytogenes and Leishmania major. To determine the role of IL-1 in the host response to tuberculosis, we infected IL-1 type I receptor-deficient (IL-1R(-/-)) mice, in which IL-1 does not exert effects, with Mycobacterium tuberculosis. IL-1R(-/-) mice were more susceptible to pulmonary tuberculosis, as reflected by an increased mortality and an enhanced mycobacterial outgrowth in lungs and distant organs, which was associated with defective granuloma formation, containing fewer macrophages and fewer lymphocytes, whereas granulocytes were abundant. Lymphocytes were predominantly confined to perivascular areas, suggesting a defective migration of cells into inflamed tissue in the absence of IL-1 signaling. Impaired host defense in IL-1R(-/-) mice was further characterized by a decrease in the ability of splenocytes to produce interferon-gamma. Analysis of these data suggests that IL-1 plays an important role in the immune response to M. tuberculosis.

Transcriptional and inflammasome‐mediated pathways for the induction of IL‐1β production by Mycobacterium tuberculosis

“…Defective granuloma formation was seen, and splenocytes of IL-1RI À/À mice produced less . These data are in contradiction with a recent study by not induce IL-1b secretion and this pathway would be absent during the anti-mycobacterial host defense, IL-1-deficient mice could not be more susceptible to TB [21]. Our study also clearly demonstrates the capacity of M. tuberculosis, either alive or heatkilled, to stimulate IL-1b synthesis in human and murine primary monocytes or macrophages.…”

“…Interestingly, although an active caspase-1 is required for the release of active IL-1b, its activation was only moderately dependent on the stimulation of cells by M. tuberculosis, due to the presence of constitutively active caspase-1 in human primary monocytes. The importance of understanding the mechanisms responsible for IL-1b production by M. tuberculosis is underlined by the fact that an intact IL-1-mediated signal is an essential component of the host defense to mycobacteria [10,21,22]. Aerogenic infection with M. tuberculosis proved fatal for IL-1RI À/À mice, resulting in a mycobacterial load increased by 2 logs in the lungs and necrotizing pneumonia [21,23].…”

“…The importance of understanding the mechanisms responsible for IL-1b production by M. tuberculosis is underlined by the fact that an intact IL-1-mediated signal is an essential component of the host defense to mycobacteria [10,21,22]. Aerogenic infection with M. tuberculosis proved fatal for IL-1RI À/À mice, resulting in a mycobacterial load increased by 2 logs in the lungs and necrotizing pneumonia [21,23]. Defective granuloma formation was seen, and splenocytes of IL-1RI À/À mice produced less .…”

“…Aerogenic infection with M. tuberculosis proved fatal for IL-1RI À/À mice, resulting in a mycobacterial load increased by 2 logs in the lungs and necrotizing pneumonia [21,23]. Defective granuloma formation was seen, and splenocytes of IL-1RI À/À mice produced less IFN-g [21].…”

“…Aerogenic infection with M. tuberculosis proved fatal for IL-1RI À/À mice, resulting in a mycobacterial load increased by 2 logs in the lungs and necrotizing pneumonia [21,23]. Defective granuloma formation was seen, and splenocytes of IL-1RI À/À mice produced less IFN-g [21]. These data are in contradiction with a recent study by Master et al, suggesting that M. tuberculosis prevents inflammasome activation and IL-1b secretion [24]: if mycobacteria would not induce IL-1b secretion and this pathway would be absent during the anti-mycobacterial host defense, IL-1-deficient mice could not be more susceptible to TB [21].…”