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

• 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
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.02120

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.