• cAMP levels regulate macrophage alternative activation marker expression

      Polumuri, Swamy; Perkins, Darren J; Vogel, Stefanie N (SAGE Publications Inc., 2020-11-26)
      The capacity for macrophages to polarize into distinct functional activation states (e.g., M1, M2) is critical to tune an inflammatory response to the relevant infection or injury. Alternative or M2 polarization of macrophages is most often achieved in vitro in response to IL-4/IL-13 and results in the transcriptional up-regulation of a constellation of characteristic M2 marker genes. In vivo, additional signals from the inflammatory milieu can further increase or decrease M2 marker expression. Particularly, activation of cAMP-generating G protein-coupled receptors is reported to increase M2 markers, but whether this is strictly dependent upon cAMP production is unclear. We report herein that increased cAMP alone can increase IL-4-dependent M2 marker expression through a PKA/C/EBPβ/CREB dependent pathway in murine macrophages.
    • Klebsiella pneumoniae induces host metabolic stress that promotes tolerance to pulmonary infection.

      Wong Fok Lung, Tania; Charytonowicz, Daniel; Beaumont, Kristin G; Shah, Shivang S; Sridhar, Shwetha H; Gorrie, Claire L; Mu, Andre; Hofstaedter, Casey E; Varisco, David; McConville, Thomas H; et al. (Elsevier, 2022-04-03)
      K. pneumoniae sequence type 258 (Kp ST258) is a major cause of healthcare-associated pneumonia. However, it remains unclear how it causes protracted courses of infection in spite of its expression of immunostimulatory lipopolysaccharide, which should activate a brisk inflammatory response and bacterial clearance. We predicted that the metabolic stress induced by the bacteria in the host cells shapes an immune response that tolerates infection. We combined in situ metabolic imaging and transcriptional analyses to demonstrate that Kp ST258 activates host glutaminolysis and fatty acid oxidation. This response creates an oxidant-rich microenvironment conducive to the accumulation of anti-inflammatory myeloid cells. In this setting, metabolically active Kp ST258 elicits a disease-tolerant immune response. The bacteria, in turn, adapt to airway oxidants by upregulating the type VI secretion system, which is highly conserved across ST258 strains worldwide. Thus, much of the global success of Kp ST258 in hospital settings can be explained by the metabolic activity provoked in the host that promotes disease tolerance.