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  • Review Article
  • Published:

The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases

Nature Reviews Rheumatology volume 12, pages 543–558 (2016)Cite this article

Subjects

Key Points

  • Macrophages and dendritic cells (DCs) are essential for the pathogenesis of rheumatoid arthritis (RA)

  • Phagocytosis of dying cells is necessary for the resolution of inflammation, and defects in this process can lead to rheumatic disease

  • Macrophage-specific and DC-specific defects in mediators of the extrinsic apoptotic pathway induce altered responses in experimental arthritis, and overexpression and/or deletion of components of the intrinsic apoptotic pathway influence the development of experimental arthritis

  • Global deletion of necroptotic signalling mediators results in a more rapid resolution of experimental arthritis, whereas macrophage-specific deletion of inhibitors of apoptosis exacerbates experimental arthritis

  • Autophagy might have a cell-specific inhibitory and proinflammatory role in RA and experimental arthritis

  • Risk polymorphisms in mediators of the extrinsic apoptotic pathway and autophagy have been identified in patients with RA

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.

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Figure 1: Extrinsic and intrinsic pathways of apoptosis.
Figure 2: Caspase 8-deficient macrophages are hyperresponsive to Toll-like receptor activation.
Figure 3: Caspase 8 is required for normal M1 macrophage polarization in vitro.
Figure 4: Caspase 8-deficient dendritic cells are hyperresponsive to Toll-like receptor activation.

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Acknowledgements

This work was supported by grants from the NIH to C.M.C. (K01AR064313), R.M.P. (AR065076, AR067687) and H.P. (AR064546, AR050250, AR054796, AI092490, HL108795), and funds provided to R.M.P. from the Pfizer Aspire award and to H.P. by the Solovy-Arthritis Research Society Chair in Medicine.

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  1. Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine, 240 East Huron Street, Chicago, 60611, Illinois, USA

    Carla M. Cuda, Richard M. Pope & Harris Perlman

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  1. Carla M. Cuda
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C.C. researched data for the article. All authors substantially contributed to discussion of content, and reviewed/edited the manuscript before submission. C.C. and H.P. wrote the article.

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Correspondence to Carla M. Cuda or Harris Perlman.

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PowerPoint slides

Glossary

Apoptosis

A process of programmed cell death

Phagocytosis

A process by which a cell engulfs bacteria, parasites, dead host cells and cellular and foreign debris.

Efferocytosis

A process similar to, yet distinct from, phagocytosis, whereby phagocytes engulf and eliminate apoptotic cells to promote the resolution of inflammation.

Splenomegaly

Abnormal enlargement of the spleen.

Lymphadenopathy

A disease characterized by abnormal size, number or consistency of lymph nodes.

Hypergammaglobulinaemia

A condition characterized by increased levels of immunoglobulins in the blood serum.

Glomerulonephritis

Acute inflammation of the kidney, typically caused by an immune response.

Proteinuria

The presence of abnormal quantities of proteins in the urine, which might indicate damage to the kidneys.

Necroptosis

A programmed form of necrosis or inflammatory cell death.

Citrullination

The conversion of the amino acid arginine within a protein to the amino acid citrulline.

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Cuda, C., Pope, R. & Perlman, H. The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases. Nat Rev Rheumatol 12, 543–558 (2016). https://doi.org/10.1038/nrrheum.2016.132

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