Myeloid cell tet methylcytosine dioxygenase 2 does not affect the host response during gram-negative bacterial pneumonia and sepsis

Tet methylcytosine dioxygenase 2 (Tet2) is an important enzyme in the demethylation of DNA. Recent evidence has indicated a role for Tet2 in the regulation of macrophage activation by lipopolysaccharide (LPS) and mice with a myeloid cell Tet2 deficiency showed enhanced lung inflammation upon local LPS administration. However, mice with a global Tet2 deficiency showed reduced systemic inflammation during abdominal sepsis. Here, we sought to determine the role of myeloid cell Tet2 in the host response during gram-negative bacterial pneumonia. To this end we infected myeloid cell specific Tet2 deficient and control mice with two common gram-negative respiratory pathogens via the airways: Pseudomonas aeruginosa (PAK, causing acute infection that remains confined in the lungs) or Klebsiella pneumoniae (causing a gradually evolving pneumonia with subsequent dissemination and sepsis) and compared bacterial loads and host response parameters between mouse strains. Bone marrow derived macrophages from myeloid Tet2 deficient mice released more interleukin-6 than control macrophages upon stimulation with PAK or K. pneumoniae. However, bacterial loads did not differ between mouse strains upon infection with viable PAK or K. pneumoniae, and neither did cytokine levels or neutrophil recruitment. In addition, in the K. pneumoniae pneumosepsis model myeloid Tet2 deficiency did not affect systemic inflammation or organ injury. Together these data strongly argue against a role for myeloid cell Tet2 in the host response during gram-negative bacterial pneumonia and pneumosepsis.
peer-reviewed