Burying the Dead: The Impact of Failed Apoptotic Cell Removal (Efferocytosis) on Chronic Inflammatory Lung Disease

doi:10.1378/chest.129.6.1673

Chest

Volume 129, Issue 6, June 2006, Pages 1673-1682

https://doi.org/10.1378/chest.129.6.1673 Get rights and content

Apoptosis and the removal of apoptotic cells (termed efferocytosis) are tightly coupled with the regulation of normal lung structure, both in the developing and adult organism. Processes that disrupt or uncouple this balance have the potential to alter normal cell turnover, ultimately resulting in the induction of lung pathology and disease. Apoptotic cells are increased in several chronic inflammatory lung diseases, including cystic fibrosis (CF), non-CF bronchiectasis, COPD, and asthma. While this may well be due to the enhanced induction of apoptosis, increasing data suggest that the clearance of dying cells is also impaired. Because efferocytosis appears to be a key regulatory checkpoint for the innate immune system, the adaptive immune system, and cell proliferation, the failure of this highly conserved process may contribute to disease pathogenesis by impeding both the resolution of inflammation and the maintenance of alveolar integrity. The recognition of impaired efferocytosis as a contributor to chronic inflammation may ultimately direct us toward the identification of new disease biomarkers, as well as novel therapeutic approaches.

Section snippets

Efferocytosis

Because the phagocytosis of apoptotic cells has distinctive morphologic features and unique downstream consequences, deCathelineau and Henson¹⁰ and Gardai et al¹¹ coined the unique term efferocytosis (taken from the Latin effero, meaning to take to the grave or to bury). During efferocytosis, large membrane ruffles sprout out from the phagocyte surface and engulf apoptotic cells into large, fluid-filled phagosomes, or “efferosomes” (Fig 1, top, A). Unlike complement or Fcγ receptor-mediated

Burying the Bodies

The most immediate consequence of efferocytosis is the physical removal of apoptotic cells before membrane permeability sets in, thus preventing the release of potentially toxic intracellular contents. This process may be particularly important in the case of neutrophils, because of their large numbers during acute inflammation, their short lifespan, and their internal stores of proteases, inflammatory mediators, and oxidants. This concern seems to be substantiated by in vitro studies³⁴ showing

Chronic Inflammatory Diseases of the Lung

Impaired efferocytosis is associated with a variety of chronic lung diseases, including cystic fibrosis (CF), non-CF bronchiectasis, COPD, asthma, and idiopathic pulmonary fibrosis (H.R. Collard; personal communication; March 2006), and indeed, it may play a role in their pathogenesis. While we will focus on the effect of impaired efferocytosis on the development of lung disease, we have no reason to presume that this mechanism is exclusive to the lung. In fact, defective efferocytosis has been

Therapeutic Implications

In patients with chronic inflammatory lung disease, ineffective efferocytosis may lead to the accumulation of apoptotic cells and the impaired regulation of the inflammatory response, and ultimately may suggest a new therapeutic target. While at this moment the demonstration of a direct role for impaired efferocytosis in disease pathogenesis is in its infancy, we think that it is reasonable to speculate on potential therapeutic approaches.

Compounds that alter the Rac-1/RhoA balance, by either

Conclusion

Cell death, removal, and replenishment are essential both to maintain homeostasis in the nondiseased organism and to appropriately regulate inflammation and tissue repair during disease. Chronic inflammation in the lung appears to be associated with the delayed removal of dying cells, which may directly impact the natural ability of the injured organism to shut down inflammation and initiate tissue repair. Further investigations will be necessary to determine whether impaired efferocytosis

ACKNOWLEDGMENT

The authors thank Dr. Moumita Ghosh for critical review of the manuscript.

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Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml)

This work was supported by an Atorvastatin Research Award (R.W.V.) sponsored by Pfizer Inc, and by grants from the National Institutes of Health grants HL072018 (R.W.V.), GM61031 and HL68864 (to P.M.H.), and HL070940 (to I.S.D).

There are no conflicts of interest for any of the authors.

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Chest

Translating Basic Research into Clinical PracticeBurying the Dead: The Impact of Failed Apoptotic Cell Removal (Efferocytosis) on Chronic Inflammatory Lung Disease

Section snippets

Efferocytosis

Burying the Bodies

Chronic Inflammatory Diseases of the Lung

Therapeutic Implications

Conclusion

ACKNOWLEDGMENT

Immunity

Cell

Chest

J Heart Lung Transplant

Cell

Blood

Curr Biol

Mol Cell

Immunity

Exp Cell Res

J Biol Chem

Blood

Curr Biol

Immunity

Immunity

Biochem Biophys Res Commun

Chest

Lancet

Respir Med

Metchnikoff and the phagocytosis theory

Nat Rev Mol Cell Biol

Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema

Am J Respir Crit Care Med

Neutrophil apoptosis in the acute respiratory distress syndrome

Am J Respir Crit Care Med

Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation

Eur Respir J

Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis

J Clin Invest

The final step in programmed cell death: phagocytes carry apoptotic cells to the grave

Essays Biochem

Possible roles for apoptosis and apoptotic cell recognition in inflammation and fibrosis

Am J Respir Cell Mol Biol

Deficientin vitroandin vivophagocytosis of apoptotic T cells by resident murine alveolar macrophages

J Immunol

Negative regulation of phagocytosis in murine macrophages by the Src kinase family member, Fgr

J Exp Med

Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system

J Immunol

Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment

Nature

Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells

J Cell Biol

Persistence of apoptotic cells without autoimmune disease or inflammation in CD14-/- mice

J Cell Biol

Translating Basic Research into Clinical Practice
Burying the Dead: The Impact of Failed Apoptotic Cell Removal (Efferocytosis) on Chronic Inflammatory Lung Disease