CD14 is a key organizer of microglial responses to CNS infection and injury

Hana Janova*, Chotima Boettcher, Inge R. Holtman, Tommy Regen, Denise van Rossum, Alexander Goetz, Anne-Sophie Ernst, Christin Fritsche, Ulla Gertig, Nasrin Saiepour, Konrad Gronke, Claudia Wrzos, Sandra Ribes, Simone Rolfes, Jonathan Weinstein, Hannelore Ehrenreich, Tobias Pukrop, Jens Kopatz, Christine Stadelmann, Gabriela Salinas-RiesterMartin S. Weber, Marco Prinz, Wolfgang Brueck, Bart J. L. Eggen, Hendrikus W. G. M. Boddeke, Josef Priller, Uwe-Karsten Hanisch

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Scopus)

Abstract

Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon -mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.

Original languageEnglish
Pages (from-to)635-649
Number of pages15
JournalGlia
Volume64
Issue number4
DOIs
Publication statusPublished - Apr-2016

Keywords

  • chemokines
  • cytokines
  • inflammation
  • monocytes
  • neutrophils
  • Toll-like receptor
  • damage
  • RECEPTOR 4
  • I INTERFERON
  • BRAIN
  • CELLS
  • LPS
  • INFLAMMATION
  • ACTIVATION
  • LIPOPOLYSACCHARIDE
  • RECRUITMENT
  • MACROPHAGES

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