Chest
Translating Basic Research into Clinical PracticeEfferocytosis and Lung Disease
Section snippets
Mechanisms of Efferocytosis
Efferocytosis is a regulated, evolutionarily conserved process requiring phagocyte migration, adhesion, and ingestion. Apoptotic cells actively recruit mononuclear phagocytes by secreting chemotaxins and further identify themselves by shifting both surface glycoprotein composition and the basal asymmetry of their membrane lipids, displaying phosphatidylserine (PS) and other molecules.6 Møs and DCs bind PS either directly, using receptors such as TIM-4 and brain angiogenesis inhibitor 1, or
Immune Consequences of Efferocytosis
Besides preventing release of alarmins during secondary necrosis, efferocytosis profoundly impacts phagocyte function.13 Efferocytosis was initially believed to be invariably antiinflammatory or tolerogenic but is now recognized to induce more complex responses. Strong evolutionary pressure has assured that efferocytosis permits maintenance of tolerance to host molecules while allowing generation of immune responses to infected apoptotic cells. How phagocytes achieve these potentially
Alveolar and Interstitial Lung Møs
Alveolar Møs (AMøs) are the most numerous professional phagocyte of the alveolar space and the most commonly studied. In healthy individuals, AMøs comprise 90% to 95% of cells recovered from BAL. Although AMøs avidly ingest many types of particles, they engulf apoptotic cells poorly when compared with other tissue Møs.8 Several factors contribute to reduced efferocytosis by AMø, including reduced adhesion, very low expression of protein kinase C βII, and inhibition by the lung collectins
COPD
COPD is increasingly recognized to result from several pathologic processes, including loss of airway luminal diameter due to mucus gland hyperplasia and peribronchial fibrosis; pan-alveolar destruction; and, recently, small airways disappearance.38 The clinical phenotype in a given patient with COPD results from variable involvement of these processes, several of which, especially emphysema, are characterized by apoptosis of lung structural cells. Neutrophils, recruited by IL-8 and by
Common Respiratory Drugs
Efferocytosis by human and murine AMøs is significantly increased by in vitro treatment with clinically relevant doses of statins, macrolides, or corticosteroids.31., 40., 42., 55., 56. In mice, this effect of statins has also been demonstrated in vivo; it appears to be mediated by RhoA inhibition (thereby allowing activation of Rac-1, which is necessary for efferocytosis).56 Corticosteroids increase AMø efferocytosis by two processes: one rapid and dependent largely on SIRPα down-regulation;
Conclusions
Enhancing the defective efferocytosis seen in multiple lung diseases and active cigarette smoking is a plausible means to arrest ongoing lung inflammation. Improved efferocytosis may contribute to beneficial actions of existing therapies, such as inhaled steroids, macrolides, and statins. Better understanding of the molecular basis for the immunomodulatory effects of efferocytosis could lead to entirely novel therapies. Further investigation is needed to determine the true impact of enhancing
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Role of sponsors: The funding agencies had no role beyond financial support in the preparation of this manuscript. The opinions expressed are those of the authors and do not reflect the position of the Department of Veterans Affairs.
Other contributions: We thank David M. Aronoff, MD; Gary
References (63)
- et al.
Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease
Chest
(2006) - et al.
Metabolic connections during apoptotic cell engulfment
Cell
(2011) - et al.
Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR
Immunity
(2009) - et al.
Cell death in the maintenance and abrogation of tolerance: the five Ws of dying cells
Immunity
(2011) - et al.
Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators
Blood
(2012) - et al.
TAM receptors are pleiotropic inhibitors of the innate immune response
Cell
(2007) - et al.
Efferocytosis is an innate antibacterial mechanism
Cell Host Microbe
(2012) - et al.
The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells
Clin Immunol
(2009) - et al.
Recognition of apoptotic cells by epithelial cells: conserved versus tissue-specific signaling responses
J Biol Chem
(2010) - et al.
Defective efferocytosis by alveolar macrophages in IPF patients
Respir Med
(2012)
Carbocisteine promotes phagocytosis of apoptotic cells by alveolar macrophages
Eur J Pharmacol
Inhaled corticosteroids and risk of pneumonia in newly diagnosed COPD
Respir Med
Role of apoptosis in amplifying inflammatory responses in lung diseases
J Cell Death
Bim siRNA decreases lymphocyte apoptosis and improves survival in sepsis
Shock
Modulation of macrophage efferocytosis in inflammation
Front Immunol
State of the art. Apoptosis and cell homeostasis in chronic obstructive pulmonary disease
Proc Am Thorac Soc
Dangerous attraction: phagocyte recruitment and danger signals of apoptotic and necrotic cells
Apoptosis
Immunobiology of the TAM receptors
Nat Rev Immunol
Tyro3 receptor tyrosine kinases in the heterogeneity of apoptotic cell uptake
Front Biosci
PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance
Nat Med
Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator-activated receptor gamma or retinoid X receptor alpha deficiency
J Immunol
The innate immune system and the clearance of apoptotic cells
J Leukoc Biol
Macrophage phagocytosis of neutrophils at inflammatory/infectious foci: a cooperative mechanism in the control of infection and infectious inflammation
J Leukoc Biol
Immune unresponsiveness to secondary heterologous bacterial infection after sepsis induction is TRAIL dependent
J Immunol
Surfactant proteins A and D suppress alveolar macrophage phagocytosis via interaction with SIRP alpha
Am J Respir Crit Care Med
Dying and necrotic neutrophils are anti-inflammatory secondary to the release of alpha-defensins
J Immunol
Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not proinflammatory to phagocytosing macrophages
J Leukoc Biol
Transcriptional and translational regulation of TGF-beta production in response to apoptotic cells
J Immunol
Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation
J Immunol
Twist mediates suppression of inflammation by type I IFNs and Axl
J Exp Med
Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling
J Exp Med
Cited by (90)
Glucocorticoid therapy for acute respiratory distress syndrome: Current concepts
2024, Journal of Intensive MedicineLong non-coding RNA (lncRNA): A potential therapeutic target in acute lung injury
2022, Genes and DiseasesCitation Excerpt :Apoptotic cells comprise many potential autoantigens and alarmins like adenosine, HSP proteins, HMG box-1 proteins. Secretion of these molecules during necrosis leads to mortality in the appropriate sepsis model, and their long-term persistence can also induce autoimmunity.98 Dysfunctional efferocytosis has been reported in many lung diseases such as asthma, COPD, and cystic fibrosis; This led to the proposal that promoting efferocytosis might arrest the progression of the disease.99
Efferocytosis in lung mucosae: implications for health and disease
2022, Immunology LettersEfferocytosis of vascular cells in cardiovascular disease
2022, Pharmacology and TherapeuticsCitation Excerpt :Another disease that is famous for being related to efferocytosis is lung disease. Defective efferocytosis and accumulated apoptotic cells in the lung are implicated in the development of lung diseases, including chronic obstructive pulmonary disease (COPD) (Lin et al., 2020; McCubbrey & Curtis, 2013; Zheng, Abou Taka, & Heit, 2021). Although it is not a “vascular cell”-initiated disease, we cite here for the example in which efferocytosis is used as a therapeutic target.
What's the deal with efferocytosis and asthma?
2021, Trends in ImmunologyCitation Excerpt :In addition to the mere clean-up function of efferocytosis, CD103+ DCs play an essential role in engulfing dying cells and cross-presenting antigens to CD8+ T cells in regional lymph nodes. Further, non-immune cells, such as airway epithelial cells and endothelial cells (Figure 4B), are crucial executioners of efferocytosis in the lung [51,52]. Thus, in a murine model of asthma, efferocytotic defects in airway epithelial cells have resulted in increased disease severity [53].
Funding/Support: This work was supported by the National Institutes of Health [Grants U01 HL098961, R01 HL056309, and R01 HL082480] and by a Research Enhancement Award Program from the Biomedical Laboratory Research and Development Service, Department of Veterans Affairs.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.