The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases

Nat Rev Rheumatol. 2016 Aug 23;12(9):543-58. doi: 10.1038/nrrheum.2016.132.

Abstract

Rheumatoid arthritis affects nearly 1% of the world's population and is a debilitating autoimmune condition that can result in joint destruction. During the past decade, inflammatory functions have been described for signalling molecules classically involved in apoptotic and non-apoptotic death pathways, including, but not limited to, Toll-like receptor signalling, inflammasome activation, cytokine production, macrophage polarization and antigen citrullination. In light of these remarkable advances in the understanding of inflammatory mechanisms of the death machinery, this Review provides a snapshot of the available evidence implicating death pathways, especially within the phagocyte populations of the innate immune system, in the perpetuation of rheumatoid arthritis and other rheumatic diseases. Elevated levels of signalling mediators of both extrinsic and intrinsic apoptosis, as well as the autophagy, are observed in the joints of patients with rheumatoid arthritis. Furthermore, risk polymorphisms are present in signalling molecules of the extrinsic apoptotic and autophagy death pathways. Although research into the mechanisms underlying these pathways has made considerable progress, this Review highlights areas where further investigation is particularly needed. This exploration is critical, as new discoveries in this field could lead to the development of novel therapies for rheumatoid arthritis and other rheumatic diseases.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy / physiology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Dendritic Cells / physiology
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism
  • Humans
  • Macrophages / physiology
  • Phagocytes / physiology*
  • Phagocytosis / physiology
  • Rheumatic Diseases / genetics
  • Rheumatic Diseases / immunology*
  • Rheumatic Diseases / metabolism*
  • Signal Transduction*
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Fadd protein, mouse
  • Fas protein, mouse
  • Fas-Associated Death Domain Protein
  • fas Receptor
  • Caspase 8