TPL-2–ERK1/2 Signaling Promotes Host Resistance against Intracellular Bacterial Infection by Negative Regulation of Type I IFN Production

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of mortality and morbidity worldwide, causing approximately 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1 and TNF-α, as well as IFN-γ and CD4+ Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I interferon have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL-10 is known to inhibit the immune response to Mtb in murine models through the negative regulation of key pro-inflammatory cytokines and the subsequent Th1 response. We show here, using a combination of transcriptomic analysis, genetics and pharmacological inhibitors that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I interferon production. The TPL-2-ERK1/2 signalling pathway regulated production by macrophages of several cytokines important in the immune response to Mtb as well as regulating induction of a large number of additional genes, many in a type I IFN dependent manner. In the absence of TPL-2 in vivo, excess type I interferon promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I interferon may promote susceptibility to this important disease.

Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells

“…This report offers additional clarity on the role of Tpl2 in M. tuberculosis infection and covers new ground that has not previously been studied by other groups, such as McNab et al, who also demonstrated Tpl2-dependent induction of IL-10 and suppression of IL-12 in macrophages by M. tuberculosis (48). Among the multiple receptors that recognize M. tuberculosis, we demonstrate that TLR2 is responsible for activation of Tpl2 and ERK in M. tuberculosis-infected macrophages ( Fig.…”

“…Prior research has not connected Tpl2-ERK signaling in macrophages with regulation of T cell responses. Indeed, one of the major issues in understanding the role of Tpl2 is that in vitro, Tpl2 deletion facilitates a more proinflammatory macrophage response (this work and reference 48), but in vivo, Tpl2 is protective against M. tuberculosis (48). These in vivo results may be confounded by a combination of different roles for Tpl2 in different cell types, making the results of systemic Tpl2 knockout difficult to interpret mechanistically.…”

Tumor Progression Locus 2-dependent Oxidative Burst Drives Phosphorylation of Extracellular Signal-regulated Kinase during TLR3 and 9 Signaling

“…We and others have previously demonstrated the critical role of Tpl2 in host defense against intracellular bacteria like Listeria monocytogenes and Mycobacterium tuberculosis (16,48). Defective ROS production in tpl2 Ϫ/Ϫ mice may contribute to decreased bacterial clearance, increased susceptibility to infection or altered redox-sensitive signaling (39,49).…”

Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

“…Accordingly, Tpl2 Ϫ/Ϫ mice are more susceptible than wild-type mice to the Th1-inducing intracellular pathogens Toxoplasma gondii (22), Listeria monocytogenes (21), and Mycobacterium tuberculosis (23). M. tuberculosis is known to induce a mixed Th1/Th17 response (reviewed in reference 56), but whether Tpl2 impacted Th17 cell differentiation in this model was not investigated.…”

“…Tpl2 has been shown to promote Th1 cell differentiation and the production of IFN-␥ (22). Therefore, Tpl2 Ϫ/Ϫ mice experience greater susceptibility and infectious burden in response to the protozoan parasite Toxoplasma gondii (22) or the intracellular bacteria Listeria monocytogenes (21) and Mycobacterium tuberculosis (23) than wild-type mice. However, Tpl2 Ϫ/Ϫ mice are resistant to endotoxin-induced septic shock due to the reduced production of TNF (20).…”