Abstract
The dwindling list of antimicrobial agents exhibiting broad efficacy against clinical strains of Mycobacterium tuberculosis (Mtb) has forced the medical community to redefine current approaches to the treatment of tuberculosis (TB). Host receptor-interacting protein kinase 3 (RIPK3) has been flagged recently as a potential target, given that it is believed to regulate necroptosis-independent signaling pathways, which have been implicated in exacerbating several inflammatory conditions and which reportedly play a role in the necrosis of Mtb-infected macrophages. To examine the therapeutic potential of inhibiting RIPK3, we infected RIPK3-deficient mice with aerosolized Mtb. We found that the loss of RIPK3 did not alter overall disease outcomes, with deficient animals harboring similar bacterial numbers in the lungs and spleens compared to their wild-type counterparts. Mtb-infected macrophages were not rescued from dying by Ripk3 deletion, nor did this affect production of the pro-inflammatory cytokine IL-1β, both in vitro and in vivo. Infiltration of immune cells into the lungs, as well as the activation of adaptive immunity, similarly was not overtly affected by the loss of RIPK3 signaling. Collectively, our data argue against a role of RIPK3 in mediating pathological inflammation or macrophage necrosis during Mtb disease pathogenesis and thus suggest that this host protein is unlikely to be an attractive therapeutic target for TB.
Highlights
The alarmingly rapid emergence of highly drug-resistant strains of Mycobacterium tuberculosis (Mtb) has given traction to therapeutic approaches that target host cellular processes rather than the pathogen itself
RIPK1 interacts with receptor-interacting protein kinase 3 (RIPK3), the best characterized role of which is the phosphorylation of mixed lineage kinase domainlike (MLKL)—a dedicated pseudokinase that is essential for the execution of a regulated necrotic form of cell death, termed necroptosis [4, 5]
We recently demonstrated that Mtb-infected human and mouse macrophages do not undergo necroptosis and that this form of cell death does not contribute to Mtb disease pathogenesis in vivo [6]
Summary
The alarmingly rapid emergence of highly drug-resistant strains of Mycobacterium tuberculosis (Mtb) has given traction to therapeutic approaches that target host cellular processes rather than the pathogen itself. The receptor-interacting protein kinase (RIPK) family comprises seven members whose defining feature is a homologous serine/threonine kinase domain, but which differ widely in terms of functional domains [1]. As their name implies, the RIPK proteins play fundamental roles in the response to intracellular and extracellular stimuli and have emerged as critical regulators of inflammatory and cell death signaling pathways, leading to intense interest in pharmacologically targeting. RIPK1 interacts with RIPK3, the best characterized role of which is the phosphorylation of mixed lineage kinase domainlike (MLKL)—a dedicated pseudokinase that is essential for the execution of a regulated necrotic form of cell death, termed necroptosis [4, 5]
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