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

Abstract

In vivo control of Mycobacterium tuberculosis (Mtb) reflects the balance between host-immunity and bacterial evasion strategies. Effector TH1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent over exuberant 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 Mtb infected macrophages stimulates IL-1β secretion, which is essential for survival in the mouse model. Why IL-1β is required for host resistance to Mtb infection is unknown. Here we show that IL-1β directly kills Mtb in murine and human macrophages and does so through the recruitment of other antimicrobial effector molecules. IL-1β 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-1β and downstream TNF production leads to caspase-dependent restriction of intracellular Mtb growth.

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

“…A recent followup study further showed that recombinant IL-1β increases both the production of TNF and upregulates the surface expression of the TNF receptor-1 (TNFR1) in macrophages. This increase in TNF signaling in turn induces caspase-3 activation and apoptosis of infected macrophages, enabling increased control of mycobacterial growth through efferocytosis (391). These studies support the idea that, in addition to directly bestowing the macrophage with antimicrobial effector molecules, apoptotic neutrophils also act as danger signal, which increases expression of proIL-1β and inflammasome components, and augments the secretion of IL-1β from infected macrophages.…”

“…However, if the bacteria manage to avoid early killing and establish infection, the NLRP3 inflammasome becomes redundant, as suggested by in vivo studies in mice, where infection is experimentally established. The most studied effector mechanism of inflammasome activation is the generation of IL-1β, and addition of recombinant IL-1β has been shown to induce phagosomal maturation, autophagy and a robust TNF response leading to increased killing of M. tuberculosis in macrophages (167,359,391). However, these studies have mainly used murine macrophages and BCG, or a model with low MOI, longer incubation times and no detectable necrosis.…”

Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

“…However, its down-regulation observed in vivo and in vitro upon MS-275 treatment, which was associated with a reduction in leukocyte infiltration in the pancreas and reduced activation of LPS-stimulated macrophages, rather supports a pro-inflammatory role of IL-6 in the tested conditions. With regard to IL-1β, while it preferentially has a pro-inflammatory role, it is worth mentioning that its up-regulation was recently shown to induce apoptosis in bacterial-infected macrophages by inducing TNF (Jayaraman et al, 2013). Although we did not detect overt cell death of macrophages upon MS-275 treatment in the short term (h) in our experimental setting, it is possible that longterm (days) MS-275 incubation during pancreatitis may promote macrophage apoptosis and, consequently, reduce the infiltration of these cells into the pancreas.…”

NR1D1 amelioratesMycobacterium tuberculosisclearance through regulation of autophagy

“…[19][20][21][22] After phagocytosis, primary stimulation of antimicrobial activity is provided by the secretion of proinflammatory cytokines TNF, IL1B, IL6, and IL12. [23][24][25] The T-cell-driven immunity amplifies the ability of macrophages to kill and digest bacteria by inducing Th1 response and augmenting its cytotoxic activity. 26,27 In order to survive within the host system and counter frontline drug regimens, Mycobacterium tuberculosis has profoundly evolved resulting in the generation of multidrug-resistant (MDR) and extremely drug-resistant (XDR) strains.…”