The lectin-like domain of thrombomodulin hampers host defence in pneumococcal pneumonia

Abstract

The lectin-like domain of thrombomodulin (TM) plays an important regulatory role in sterile inflammatory conditions, but its role in severe Gram-positive infectious disease is unknown. Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The aim of this study was to determine the role of the lectin-like domain of TM in murine pneumococcal pneumonia.Wild-type (WT) mice and mice lacking the lectin-like domain of TM (TM LeD/LeD ) were infected intranasally with viable S. pneumoniae and either observed in a survival study or euthanised 6, 24 or 48 h after infection. TM LeD/LeD mice had a markedly better survival in pneumococcal pneumonia when compared with WT mice. At 48 h post-infection with S. pneumoniae, TM LeD/LeD mice had lower bacterial loads in blood and liver, and exhibited less pulmonary inflammation, as shown by having less lung histopathology, less neutrophil influx and lower cytokine and chemokine levels. Plasma levels of pro-inflammatory cytokines were also reduced in TM LeD/LeD mice after exposure to the infection.Deletion of the lectin-like domain of TM improves the host defence in pneumococcal pneumonia. The lectin-like domain of TM may have a differential role in response to Grampositive or Gram-negative bacteria.

The endothelial protein C receptor and activated protein C play a limited role in host defense during experimental tuberculosis

“…Mice with a mutation in the TM-gene resulting in minimal capacity for APC generation (TM pro/pro -mice) demonstrated uncontrolled lung inflammation, including higher lung weights, a diminished capacity to form well-shaped granulomas and elevated levels of pro-inflammatory cytokines, which was accompanied by a reduced survival 16 . Of note, TM pro/pro -mice have an intact lectin-like domain of thrombomodulin 17 , of which host-protective, anti-inflammatory effects have been described as well 18,19 . Little knowledge exists about the possible direct role of APC and its receptor EPCR during pulmonary TB.…”

Mice Lacking the Lectin-Like Domain of Thrombomodulin Are Protected Against Melioidosis

“…TM LeD/LeD mice also exhibited a more severe phenotype in comparison with WT mice in response to experimentally induced murine arthritis (6), ischemia-reperfusion lung injury (13), shiga toxin-associated HUS (14), and diabetic glomerulopathy (15). In contrast, our laboratory recently reported that TM LeD/LeD mice have improved survival and diminished bacterial growth and dissemination during Gram-positive pneumonia caused by S. pneumoniae (17). Interestingly, administration of recombinant soluble TM lectin-like domain resulted in enhanced bacterial clearance and dramatically improved survival after intraperitoneal infection with the Gram-negative pathogen K. pneumoniae (7).…”

“…Although the function of the lectin-like domain of TM has been studied in models of sterile inflammation (6-8, 11, 13, 14) and Gram-positive infection (17), the role of this TM domain in Gram-negative infection has hitherto not been reported.…”

“…In contrast to the preceding compelling observations, lack of the lectin-like domain of TM was beneficial in the host response to pneumonia caused by the Gram-positive bacterium Streptococcus pneumoniae. Indeed, infected TM LeD/LeD mice had a significant survival advantage, lower bacterial loads, and less pulmonary inflammation as compared with WT mice (17).…”

Recombinant soluble thrombomodulin: coagulation takes another chance to reduce sepsis mortality

“…Why would thrombomodulin work while activated protein C (and other interventions aimed at restoration of physiological anticoagulant pathways) failed? First, thrombomodulin has unique and distinct properties aimed at both the coagulation and inflammation systems, many of which are independent of the actions of activated protein C. Thrombomodulin (CD141) is a transmembrane multidomain glycoprotein receptor that is expressed primarily on vascular endothelial cells but also on monocytes, neutrophils, osteoblasts, synovial cells, and dendritic cells . Soluble thrombomodulin encompasses several domains, including a lectin‐like domain, and six epidermal growth factor (EGF)‐like repeats .…”