RANKL inhibits macrophage proinflammatory Toll-like receptor 2 and 4 signaling and impairs killing of intracellular bacteria
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Abstract Monocyte-macrophage lineage cells, crucial components of the innate immune system, can uniquely form bone-resorbing osteoclasts upon exposure to the cytokine receptor activator of nuclear factor κB ligand (RANKL) in the bone microenvironment. Recent studies have also begun to uncover extensive extraskeletal roles of RANKL. However, how monocyte-macrophage lineage cells respond to RANKL outside of the bone, and the impact that this signaling pathway exerts on the host immune response, is not fully understood. In this study, we sought to define how RANKL exposure shapes the macrophage inflammatory response to pathogens by using the model intracellular bacteriumserovar Typhimurium, which coopts macrophages to cause life-threatening infections. We found that exposing both mouse and human macrophages to subosteoclastogenic levels of RANKL increased intracellularserovar Typhimurium burdens and decreased proinflammatory cytokine production. RNA sequencing revealed downregulation of pattern recognition receptor signaling pathways in RANKL-treated macrophages during the early stages of infection. Therefore, we hypothesized that RANKL impairs pattern recognition receptor–dependent signaling pathways that are important for proinflammatory cytokine production. We discovered that RANKL-treated macrophages exhibit reduced nuclear factor κB and interferon regulatory factor 3 activation, specifically in response to Toll-like receptor 2 (TLR2) and TLR4 stimulation. We determined that
Abstract
Abstract Monocyte-macrophage lineage cells, crucial components of the innate immune system, can uniquely form bone-resorbing osteoclasts upon exposure to the cytokine receptor activator of nuclear factor κB ligand (RANKL) in the bone microenvironment. Recent studies have also begun to uncover extensive extraskeletal roles of RANKL. However, how monocyte-macrophage lineage cells respond to RANKL outside of the bone, and the impact that this signaling pathway exerts on the host immune response, is not fully understood. In this study, we sought to define how RANKL exposure shapes the macrophage inflammatory response to pathogens by using the model intracellular bacteriumserovar Typhimurium, which coopts macrophages to cause life-threatening infections. We found that exposing both mouse and human macrophages to subosteoclastogenic levels of RANKL increased intracellularserovar Typhimurium burdens and decreased proinflammatory cytokine production. RNA sequencing revealed downregulation of pattern recognition receptor signaling pathways in RANKL-treated macrophages during the early stages of infection. Therefore, we hypothesized that RANKL impairs pattern recognition receptor–dependent signaling pathways that are important for proinflammatory cytokine production. We discovered that RANKL-treated macrophages exhibit reduced nuclear factor κB and interferon regulatory factor 3 activation, specifically in response to Toll-like receptor 2 (TLR2) and TLR4 stimulation. We determined that prior RANKL exposure decreases abundance of the TLR2 and TLR4 adaptor proteins TRAM (TRIF-related adaptor molecule) and TIRAP (TIR domain–containing adaptor protein). Together, these data suggest that RANKL exposure negatively impacts the macrophage TLR-mediated inflammatory response to bacteria.