Regulation and Function of the Caspase-1 in an Inflammatory Microenvironment

J Invest Dermatol. 2015 Aug;135(8):2012-2020. doi: 10.1038/jid.2015.119. Epub 2015 Mar 27.

Abstract

The inflammasome is a complex of proteins that has a critical role in mounting an inflammatory response in reply to a harmful stimulus that compromises the homeostatic state of the tissue. The NLRP3 inflammasome, which is found in a wound-like environment, is comprised of three components: the NLRP3, the adaptor protein ASC and caspase-1. Interestingly, although ASC levels do not fluctuate, caspase-1 levels are elevated in both physiological and pathological conditions. Despite the observation that merely raising caspase-1 levels is sufficient to induce inflammation, the crucial question regarding the mechanism governing its expression is unexplored. We found that, in an inflammatory microenvironment, caspase-1 is regulated by NF-κB. Consistent with this association, the inhibition of caspase-1 activity parallels the effects on wound healing caused by the abrogation of NF-κB activation. Surprisingly, not only does inhibition of the NF-κB/caspase-1 axis disrupt the inflammatory phase of the wound-healing program, but it also impairs the stimulation of cutaneous epithelial stem cells of the proliferative phase. These data provide a mechanistic basis for the complex interplay between different phases of the wound-healing response in which the downstream signaling activity of immune cells can kindle the amplification of local stem cells to advance tissue repair.

Publication types

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

MeSH terms

  • Animals
  • Caspase 1 / physiology*
  • Caspase 8 / genetics
  • Caspase 8 / physiology
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Cellular Microenvironment / physiology*
  • Dermatitis / pathology*
  • Dermatitis / physiopathology*
  • Disease Models, Animal
  • Homeostasis / physiology
  • In Vitro Techniques
  • Keratinocytes / pathology*
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / physiology
  • Signal Transduction / physiology
  • Wound Healing / physiology

Substances

  • NF-kappa B
  • Caspase 8
  • Caspase 1