Toll-like receptor responses are shaped by distinct MAPK activation profiles

Abstract

Abstract Toll-like receptors (TLRs) are key sensors of infection and injury, and are critical inducers of inflammation. TLR-induced activation of the NF-κB and MAPK pathways promotes the secretion of mediators of inflammation such as cytokines and chemokines. Control of cytokine production is critically important, as unnecessary inflammatory responses can lead to tissue damage, while insufficient inflammatory responses can lead to susceptibility to infection. Previous studies showed that TLR4 uses distinct NF-κB and MAPK activation properties to discriminate between low and high concentrations of ligand, triggering cytokine production only at ligand concentrations that activate both pathways. The switch-like activation of MAPKs by TLR4 establishes an inflammatory threshold for ligand concentrations that facilitates threat discrimination. Using murine macrophages, we reveal that MAPK activation properties are TLR-specific, and that switch-like MAPK activation is not a general feature of all TLRs. Consequently, certain TLRs do not have an inflammatory threshold of ligand concentration and may not effectively filter signal from noise. The activation properties of the ERK pathway, rather than messenger RNA levels, dictate the patterns of TNFα cytokine secretion for all TLRs examined. We demonstrate that the TLR4 inflammatory threshold can be modulated by costimulation with granulocyte-macrophage colony-stimulating factor in an ERK-dependent manner. We show that deletion of BCL-3 changes the TLR4-induced ERK pathway activation properties from switch-like to gradual and lowers the activation threshold. We reveal that different TLRs have different capacities to discriminate threats based on ligand concentration, and that ERK pathway activation properties can be altered to change the cellular decision to initiate inflammation.