IL-1b Promotes Antimicrobial Immunity in Macrophages by Regulating TNFR Signaling and Caspase-3 Activation

In vivo control of Mycobacterium tuberculosis reflects the balance between host immunity and bacterial evasion strategies. Effec-tor Th1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent overexuberant inflammation. One key immunoregulatory molecule is Tim3. Although Tim3 is generally recognized to down-regulate Th1 responses, we recently described that its interaction with Galectin-9 expressed by M. tuberculosis–infected macro-phages stimulates IL-1b secretion, which is essential for survival in the mouse model. Why IL-1b is required for host resistance to M. tuberculosis infection is unknown. In this article, we show that IL-1b directly kills M. tuberculosis in murine and human macrophages and does so through the recruitment of other antimicrobial effector molecules. IL-1b directly augments TNF signaling in macrophages through the upregulation of TNF secretion and TNFR1 cell surface expression, and results in activation of caspase-3. Thus, IL-1b and downstream TNF production lead to caspase-dependent restriction of intracellular M. tuberculosis growth. H ost resistance to Mycobacterium tuberculosis relies on the cooperation between innate and adaptive immunity. The factors that drive this cooperation involve cytokines secreted by Th1 cells through cell contact–dependent signals and myeloid cells that are activated by Th1 cells to produce antimi-crobial effector molecules. Of particular note, IFN-g and TNF are produced by M. tuberculosis–specific Th1 cells and activate infected macrophages (Mw) to induce intracellular mediators such as NO and promote changes in intracellular physiology, including phagolysosomal fusion (1, 2). Both IFN-g 2/2 (2/2 , knockout) and nitric oxide synthase-2 (NOS2 2/2) mice are extremely susceptible to M. tuberculosis, which indicates the crucial role of IFN-g and NO in immunity against tuberculosis (3–5). TNF plays a key role in granuloma formation, thereby molding the extracellular milieu in which M. tuberculosis–infected Mw interact with M. tubercu-losis–specific T cells. TNF blockade in M. tuberculosis–infected wild-type (WT) mice or latently infected humans exacerbates disease (6, 7). Together, IFN-g and TNF play an important part in shaping the unique microenvironment in lung granulomas and differentially modulate effector T cell immune reactivity. Following resolution and clearance of infection, effector T cells are deleted, which prevents excessive tissue inflammation and development of immunopathology. The expression of cell surface inhibitory receptors, such as T cell–Ig and mucin-domain–con-taining molecule-3 (Tim3), negatively regulates effector Th1 cells (8). In addition to its role in T cell exhaustion, we previously described that Tim3 expressed by T cells interacts with Gal9 expressed by infected Mw …