The TLR4-MyD88 Signaling Axis Regulates Lung Monocyte Differentiation Pathways in Response to 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 l...

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Published in:	Frontiers in immunology Vol. 11; p. 2120
Main Authors:	Sánchez-Tarjuelo, Rodrigo, Cortegano, Isabel, Manosalva, Juliana, Rodríguez, Mercedes, Ruíz, Carolina, Alía, Mario, Prado, María Carmen, Cano, Eva M, Ferrándiz, María José, de la Campa, Adela G, Gaspar, María Luisa, de Andrés, Belén
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 16-09-2020
Subjects:	Administration, Intranasal Animals Bacterial Load Cytokines - biosynthesis Immunity, Innate Immunology innate immune responses Lung - immunology Lung - pathology Macrophages, Alveolar - immunology Mice monocyte differentiation Monocytes - immunology Monocytes - pathology MyD88 Myeloid Differentiation Factor 88 - deficiency Myeloid Differentiation Factor 88 - physiology Myelopoiesis - physiology Neutrophil Infiltration Pneumonia, Pneumococcal - immunology Pneumonia, Pneumococcal - pathology Reactive Oxygen Species - metabolism ROS S. pneumoniae Signal Transduction - physiology Streptococcus pneumoniae - immunology Th1 Cells - immunology TLR4 Toll-Like Receptor 4 - deficiency Toll-Like Receptor 4 - physiology S. pneumoniae monocyte differentiation MyD88 TLR4 innate immune responses ROS
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Summary:	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 , 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 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 , which involves both the MyD88 and TRIF (Toll/IL-1R domain-containing adaptor-inducing IFN-β) dependent pathways.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Silvia Sánchez-Ramón, Complutense University of Madrid, Spain This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology Reviewed by: Alex De Vos, Amsterdam University Medical Center (UMC), Netherlands; Anja Andrea Kühl, Charité – Universitätsmedizin Berlin, Germany
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2020.02120