Murine β-defensin 2 promotes TLR-4/MyD88-mediated and NF-κB-dependent atypical death of APCs via activation of TNFR2

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Abstract
Mammalian antimicrobial peptides, including β-defensins, represent an ancient arm of innate immunity designed to directly neutralize invading microbes. Previously, we demonstrated that murine β-defensin 2 (mDF2β) also acted as an endogenous ligand for TLR-4-activating maturation of dendritic cells (DCs). Herein, we report that this TLR-4 –dependent activation leads to induction of an atypical cell death that is unexpectedly exaggerated by the inhibition of caspases. Experiments using APCs with nonfunctional TNF-α or its receptors suggest that this is a NF-κB- and TNF-α-dependent process that does not require TNFR1. We demonstrate that mDF2β triggers a TNFR2-mediated signaling cascade of “self-destruction” through up-regulation of membrane-bound TNF-α and TNFR2. This appears not to be an isolated phenomenon, as human synthetic β-defenisn 3 was also able to activate and kill DCs. We propose that β-defenins may play an important immunoregulatory role as controllers of the natural process of elimination of activated APCs.
Funding Information
  • Intramural Research Program
  • NIH
  • NIA