The TLR4-MyD88 Signaling Axis Regulates Lung Monocyte Differentiation Pathways in Response to Streptococcus pneumoniae

Abstract

Streptococcus pneumoniae is the main cause of bacterial pneumonia, a condition that currently produces significant global morbidity and mortality. The initial immune response to this bacterium occurs when the innate system recognizes common motifs expressed by many pathogens, events driven by pattern recognition receptors like the Toll-like family receptors (TLRs). In this study, lung myeloid-cell populations responsible for the innate immune response (IIR) against S. pneumoniae, and their dependence on the TLR4-signaling axis, were analyzed in TLR4 −/− and Myeloid-Differentiation factor-88 deficient (MyD88 −/−) mice. Neutrophils and monocyte-derived cells were recruited in infected mice 3-days post-infection. Compared to wild-type mice, there was an increased bacterial load in both these deficient mouse strains and an altered IIR, although TLR4 −/− mice were more susceptible to bacterial infection. These mice also developed fewer alveolar macrophages, weaker neutrophil infiltration, less Ly6C high monocyte differentiation and a disrupted classical and non-classical monocyte profile. The pro-inflammatory cytokine profile (CXCL1, TNF-α, IL-6, and IL-1β) was also severely affected by the lack of TLR4 and no induction of Th1 was observed in these mice. The respiratory burst (ROS production) after infection was profoundly dampened in TLR4 −/− and MyD88 −/− mice. These data demonstrate the complex dynamics of myeloid populations and a key role of the TLR4-signaling axis in the IIR to S. pneumoniae, which involves both the MyD88 and TRIF (Toll/IL-1R domain-containing adaptor-inducing IFN-β) dependent pathways.

Extracellular CIRP Induces an Inflammatory Phenotype in Pulmonary Fibroblasts via TLR4

“…Inflammatory fibroblasts persistently activate the fibroblasts in an autocrine/paracrine manner in the lungs, resulting in pulmonary fibrosis (63)(64)(65). The proinflammatory role of TLR4-MD2 complex and Myd88 signaling pathway in the lungs has also been evaluated (66)(67)(68)(69) and associated with the fibrotic process leading to pulmonary fibrosis (60,(70)(71)(72)(73)(74). In our study, we found that eCIRP induces proinflammatory cytokines and their pathways in pulmonary fibroblasts in a TLR4 dependent manner.…”

Toll-Like Receptors in Acute Kidney Injury

“…TLR4 is a key molecule involved in the pathogenesis of inflammatory diseases [ 63 , 64 ]. Indeed, reports on PAMPs recognition mediated by TLR4 strongly support its role against different pathogens, mediating both secretion of proinflammatory cytokines and chemotactic factors that mediate the local recruitment of immune cells, including neutrophils and macrophages [ 46 , 65 , 66 , 67 ]. Additionally, TLR4 recognition of DAMPs in damaged tissues further contributes to local inflammation and fibrosis [ 68 ].…”

“…Upon infection, bone marrow (BM)-derived myeloid cells are produced and then recruited to damaged tissues where they differentiate to dendritic cells and macrophages, contributing to the initial local inflammatory response [ 70 , 71 ]. Additionally, BM-derived monocytes with a patrolling profile are abundant during the late stages of local inflammatory processes and participate in its resolution and tissue repair, but also may produce fibrosis [ 64 , 65 , 71 ]. Alterations in vascular permeability mediated by TLR4 interactions allow infiltration of circulating cells in the injured tissues.…”

Antimicrobial and Anti-Inflammatory Activity of Apple Polyphenol Phloretin on Respiratory Pathogens Associated With Chronic Obstructive Pulmonary Disease

“…S. pneumoniae is a gram-positive bacterium that does not express LPS. However, TLR2 and TLR4 recognize lipoteichoic acid, present on its cell wall, and pneumolysin, which it secretes ( Sánchez-Tarjuelo et al., 2020 ). Upon TLR activation, macrophages secrete cytokines to stimulate activation and migration of neutrophils and other immune cells to the site of injury ( Wu et al., 2009 ).…”