Double-Stranded RNA Interacts With Toll-Like Receptor 3 in Driving the Acute Inflammatory Response Following Lung Contusion

Abstract

Objectives Lung contusion (LC) is a major risk factor for the development of acute respiratory distress syndrome (ARDS). We set to determine the role of TLR3 and the binding of dsRNA in the pathogenesis of sterile injury following lung contusion. Methods TLR3 expression was analyzed in post-mortem lung samples from patients with LC. Unilateral LC was induced in TLR3 (−/−), TRIF (−/−), and WT mice; subsequently, lung injury and inflammation were evaluated. Apoptotic indices, phagocytic activity and phenotypic characterization of the macrophages were determined. Double stranded (ds) RNA in BAL and serum samples following LC were measured. A TLR3/dsRNA ligand inhibitor was injected into WT mice prior to LC. Measurements and Main Results TLR3 expression was higher in patients and WT mice with LC. The degree of lung injury, inflammation, and macrophage apoptosis was reduced in TLR3 (−/−), TRIF (−/−), and WT mice with TLR3 antibody neutralization. Alveolar macrophages from TLR3 (−/−) mice had a lower early apoptotic index, a predominant M2 phenotype and increased surface translocation of TLR3 from the endosome to the surface. When compared to viral activation pathways, lung injury in LC demonstrated increased p38 MAPK, ERK1/2 phosphorylation with inflammasome activation without a corresponding increase in NF-kB or Type-1 Interferon production. Additionally, pretreatment with TLR3/dsRNA ligand inhibitor led to a reduction in injury, inflammation, and macrophage apoptosis. Conclusions We conclude that the interaction of dsRNA from injured cells with TLR3 drives the acute inflammatory response following LC.

TLR3 absence confers increased survival with improved macrophage activity against pneumonia

“…The incidence of ventilator-associated pneumonia (VAP) has steadily increased despite the introduction of the VAP bundle in the care of critically ill patients (2,3). Lung contusion (LC) is the primary cause of mortality following blunt chest trauma and blast explosions, while being an independent risk factor for the development of acute respiratory distress syndrome and VAP (4). Klebsiella pneumoniae (KP) is a capsulated gram-negative pathogen that causes a significant proportion of community-acquired and hospital-acquired pneumonia (5,6).…”

“…Pattern recognition receptors (PRRs), such as those classified under the toll-like receptor (TLR) family, consisting of 10 highly homologous TLRs in humans, are involved in detection and response (8,9), often acting through inflammatory pathways directed by NF-κB. TLRs in alveolar macrophages recognize the molecular constituents of pathogens and activate the host's innate immune responses (4). TLR3 is considered a pathogen recognition molecule associated with viral infections, with double-stranded RNA (dsRNA) serving as its sole ligand (10,11).…”

“…In addition, TLR3 activation promotes the systemic hyperinflammatory response observed during sepsis (12). We have recently demonstrated that TLR3, independent of a type I IFN response, also functions in initiation and maintenance of acute inflammatory responses following LC (4). Although these studies have indicated a role for TLR3, the precise nature Toll-like receptor 3 (TLR3) is a pathogen recognition molecule associated with viral infection with double-stranded RNA (dsRNA) as its ligand.…”

Toll‐like receptors: The role in bladder cancer development, progression and immunotherapy

“…PAMPs are highly conserved structures in micro‐organisms and are essential for their survival . The best known examples of PAMPs include lipopolysaccharide (LPS) of Gram‐negative bacteria, peptidoglycans (PG) of Gram‐positive bacteria, bacterial flagellin, unmethylated CpG motif of bacterial and viral DNA, viral single‐stranded RNAs (ssRNA) and viral double‐stranded RNA (dsRNA) which are recognized by TLR4, TLR2, TLR5, TLR9, TLR7 and TLR3, respectively (Table ).…”

“…13 PAMPs are highly conserved structures in micro-organisms and are essential for their survival. 14 Gram-negative bacteria, 15 peptidoglycans (PG) of Gram-positive bacteria, 16 bacterial flagellin, 17 unmethylated CpG motif of bacterial and viral DNA, 18 viral single-stranded RNAs (ssRNA) 19 and viral double-stranded RNA (dsRNA) 20 which are recognized by TLR4, TLR2, TLR5, TLR9, TLR7 and TLR3, respectively ( Table 1). TLRs have immunoadjuvant ability and express on antigen-presenting cells (APCs), including macrophages or dendritic cells (DCs).…”