Alpha-1 Antitrypsin Inhibits ATP-Mediated Release of Interleukin-1β via CD36 and Nicotinic Acetylcholine Receptors

Front Immunol. 2018 Apr 25:9:877. doi: 10.3389/fimmu.2018.00877. eCollection 2018.

Abstract

While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.

Keywords: CD36; CHRNA10; CHRNA7; CHRNA9; P2X7 receptor; calcium-independent phospholipase A2β; inflammasome; interleukin-1β.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • CD36 Antigens / metabolism
  • Humans
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Interleukin-1beta / immunology*
  • Interleukin-1beta / metabolism
  • Leukocytes, Mononuclear
  • Primary Cell Culture
  • Rats
  • Receptors, Purinergic P2X7 / metabolism
  • Systemic Inflammatory Response Syndrome / immunology*
  • U937 Cells
  • alpha 1-Antitrypsin / immunology
  • alpha 1-Antitrypsin / metabolism*

Substances

  • CD36 Antigens
  • IL1B protein, human
  • Inflammasomes
  • Interleukin-1beta
  • P2RX7 protein, human
  • Receptors, Purinergic P2X7
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin
  • Adenosine Triphosphate