Macrophage p38 mitogen-activated protein kinase activity regulates invariant natural killer T-cell responses during Borrelia burgdorferi infection

J Infect Dis. 2012 Jul 15;206(2):283-91. doi: 10.1093/infdis/jis332. Epub 2012 May 2.


The interaction of macrophages with infectious agents leads to the activation of several signaling cascades, including mitogen-activated protein (MAP) kinases, such as p38. We now demonstrate that p38 MAP kinase-mediated responses are critical components to the immune response to Borrelia burgdorferi. The pharmacological and genetic inhibition of p38 MAP kinase activity during infection with the spirochete results in increased carditis. In transgenic mice that express a dominant negative form of p38 MAP kinase specifically in macrophages, production of the invariant natural killer T (iNKT) cell-attracting chemokine MCP-1 and of the antigen-presenting molecule CD1d are significantly reduced. The expression of the transgene therefore results in the deficient infiltration of iNKT cells, their decreased activation, and a diminished production of interferon γ (IFN-γ), leading to increased bacterial burdens and inflammation. These results show that p38 MAP kinase provides critical checkpoints for the protective immune response to the spirochete during infection of the heart.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1d / genetics
  • Antigens, CD1d / metabolism
  • Borrelia burgdorferi*
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • Gene Expression Regulation
  • Heart Diseases / etiology
  • Heart Diseases / pathology
  • Homeostasis
  • Imidazoles / pharmacology
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / physiology*
  • Lyme Disease / complications
  • Lyme Disease / immunology*
  • Lyme Disease / pathology
  • Macrophages / enzymology*
  • Mice
  • Mice, Transgenic
  • Pyridines / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Antigens, CD1d
  • CD11b Antigen
  • Imidazoles
  • Pyridines
  • Interferon-gamma
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580