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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice

Published on: April 21, 2015

CD14 signaling restrains chronic inflammation through induction of p38-MAPK/SOCS-dependent tolerance

Bikash Sahay1, Rebeca L Patsey, Christian H Eggers

  • 1Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.

Plos Pathogens
|December 17, 2009
PubMed

Insights

CD14 is not essential for initiating inflammatory responses to Borrelia burgdorferi. Its absence alters PI3K/AKT/p38-MAPK signaling, impairing negative regulation and leading to persistent inflammation, challenging current immune response models.

Area of Science:

  • Immunology
  • Microbiology
  • Cellular Signaling

Background:

  • Current models highlight CD14 and p38-MAPK in microbial recognition and pro-inflammatory signaling via TLRs.
  • The role of CD14 in initiating inflammatory responses and its interaction with signaling pathways requires further elucidation.

Purpose of the Study:

  • To investigate the role of CD14 in the immune response to live Borrelia burgdorferi.
  • To determine the impact of CD14 deficiency on TLR2 signaling and downstream inflammatory pathways.
  • To explore the involvement of PI3K/AKT/p38-MAPK signaling in CD14-independent immune responses.

Main Methods:

  • Utilized CD14-deficient and CD14-expressing macrophages.
  • Stimulated cells with live Borrelia burgdorferi.
  • Analyzed PI3K/AKT/p38-MAPK signaling pathways, including lipid raft localization and protein phosphorylation.
  • Assessed negative regulators of TLR signaling (SOCS1, SOCS3, CIS).
  • Employed shRNA and pharmacological inhibitors to modulate p38 activity.

Main Results:

  • Live Borrelia burgdorferi triggered inflammatory responses even in CD14-deficient macrophages.
  • CD14 deficiency led to altered PI3K/AKT/p38-MAPK signaling, including increased PI3K in lipid rafts and hyperphosphorylated AKT.
  • Reduced p38 activation and impaired negative regulation by SOCS1, SOCS3, and CIS were observed in CD14-deficient cells.
  • These signaling alterations resulted in compromised macrophage tolerance and more severe, persistent inflammation.
  • Inhibition of p38 in CD14-expressing cells mimicked the aberrant signaling and heightened cytokine production.

Conclusions:

  • CD14 is not solely responsible for initiating inflammatory responses to Borrelia burgdorferi.
  • CD14 deficiency disrupts PI3K/AKT/p38-MAPK signaling and impairs negative feedback, leading to uncontrolled inflammation.
  • Aberrant immune regulation due to CD14/p38-MAPK pathway perturbation may contribute to chronic inflammatory conditions.

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