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Blood, 26 February 2009, Vol. 113, No. 9, pp. 1871-1872.
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PHAGOCYTES & GRANULOCYTES
Comment on Fernandez-Boyanapalli et al, page 2047
Long-lived life: a detriment
Laurence A. Boxer
UNIVERSITY OF MICHIGAN
In this issue of Blood, Fernandez-Boyanapalli and colleagues report that macrophages isolated from X-linked CGD mice exhibit decreased recognition and removal of apoptotic inflammatory cells secondary to attenuated endogenous IL-4 production.
Chronic granulomatous disease (CGD) involving either the membrane or the cytosolic components of the phagocyte NADPH oxidase results from defective generation of superoxide and downstream reactive oxygen species (ROS). The hallmark of the disorder is the predisposition to recurrent bacterial and fungal infections from catalase positive organisms. This is attributable to the lack of a functional NADPH oxidase. Independently, the disorder is also characterized by overexuberant sterile inflammation and a risk for autoimmune disorders, such as inflammatory bowel disease, rheumatoid arthritis, discoid lupus erythematosus, and chorioretinitis.1 In hematoxylin and eosin–stained sections from patients, macrophages may contain a golden pigment and often form diffuse granulomata, giving CGD its descriptive name.
Neutrophils from CGD patients are able to ingest microorganisms and efficiently dispose of catalase negative bacteria but there is evidence of delayed apoptosis.2 The long-lived neutrophils express reduced level of phosphatidylserine (PS), resulting in their deficient recognition by macrophages.3 Both delayed neutrophil apoptosis and deficient PS exposure result from the loss of NADPH oxidase function. The failure to clear the CGD neutrophils leads to prolonged release of intracellular constituents, such as serine proteases that contribute to the ongoing inflammation (see figure).
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Mechanism of delayed CGD neutrophil apoptosis. CGD neutrophils undergo normal rolling and adhesion onto activated endothelium. The neutrophils then undergo diapedesis in response to chemotactic stimuli into tissue. The neutrophils are able to ingest bacteria but manifest impaired apoptosis accompanied by prolonged release of proteases into tissue from primary granules, thereby generating sterile inflammation. The CGD macrophage fails to ingest the CGD neutrophil because of reduced exposure of phosphatidylserine (PS) on the neutrophil membrane. In turn, the failure to express normal amounts of PS leads to failure to activate phosphatidylserine receptors (PSRs) on the CGD macrophage, leading to attenuated production of endogenous IL-4, a required cytokine necessary to initiate stimulus-response coupling required for macrophage activation. Professional illustration by Paulette Dennis.
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In a set of novel experiments by Fernandez-Boyanapalli et al, CGD macrophages were shown to be impaired in their ability to recognize and clear apoptotic cells in a process independent of NADPH oxidase activity.4 Previous studies have shown that activation of wild-type macrophages with exogenous interleukin (IL)–4, IL-13, IL-10, or macrophage colony-stimulating factor (M-CSF) enhances their ability to ingest apoptotic cells.5–7 In this study, the lack of endogenous production of only IL-4 resulted in defective stimulus-response coupling by X-linked CGD macrophages compared with wild-type macrophages. Other investigations have shown that exogenous IL-4 coordinately stimulates both 12/15-lipoxygenase activity and up-regulates peroxisome proliferator-activated receptor (PPAR) expression and/or activity.8 In turn, PPAR is required for efficient removal of apoptotic cells by macrophages. The authors observed that use of rosiglitazone, a PPAR activator, could normalize the capacity of X-linked CGD macrophages to ingest apoptotic cells. Furthermore, the authors newly described that IL-4 could directly increase 12/15-lipoxygenase activity, leading to 12-HETE production upstream of PPAR and thereby signaling PPAR activation. This novel pathway critical to wild-type macrophage activation is required for ingesting apoptotic neutrophils. In contrast, the pathway is defective in the X-linked CGD macrophage.
One of the biochemical hallmarks of the CGD neutrophil is the deficient expression of PS, which is required to activate macrophages.9 The authors show that injection of PS in vivo restored IL-4–dependent X-linked CGD macrophages and the ability of the macrophage to clear apoptotic cells. The implications from this work suggest that the CGD neutrophil remains long-lived in the tissue milieu because of its own intrinsic inability to generate free radicals and to be cleared efficiently by CGD macrophages deficient in IL-4 production. What remains to be clarified is how the defective macrophage function contributes to the formation of the granulomata, the hallmark of the disorder, and predisposes the host to autoimmune syndromes.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Segal BH, Leto TL, Gallin JI, et al. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine. 2000;79:170–200.[CrossRef][Medline]
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- Yamamoto A, Taniuchi S, Tsuji S, et al. Role of reactive oxygen species in neutrophil apoptosis following ingestion of heat-killed Staphylococcus aureus. Clin Exp Immunol. 2002;129:479–484.[CrossRef][Medline]
[Order article via Infotrieve]
- Hampton MB, Vissers MC, Kennan JI, et al. Oxidant-mediated phosphatidylserine exposure and macrophage uptake of activated neutrophils: possible impairment in chronic granulomatous disease. J Leukoc Biol. 2002;71:775–781.[Abstract/Free Full Text]
- Fernandez-Boyanapalli RF, Frasch SC, McPhillips K, et al. Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4. Blood. 2009;113:2047–2055.[Abstract/Free Full Text]
- Montaner LJ, da Silva RP, Sun J, et al. Type 1 and type 2 cytokine regulation of macrophage endocytosis: differential activation by IL-4/IL-13 as opposed to IFN-gamma or IL-10. J Immunol. 1999;162:4606–4613.[Abstract/Free Full Text]
- Ogden CA, Pound JD, Batth BK, et al. Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt's lymphoma. J Immunol. 2005;174:3015–3023.[Abstract/Free Full Text]
- Sampson LL, Heuser J, Brown EJ. Cytokine regulation of complement receptor-mediated ingestion by mouse peritoneal macrophage. M-CSF and IL-4 activate phagocytosis by a common mechanism requiring autostimulation by IFN-beta. J Immunol. 1991;146:1005–1013.[Abstract]
- Huang JT, Welch JS, Ricote M, et al. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxyganase. Nature. 1999;400:378–382.[CrossRef][Medline]
[Order article via Infotrieve]
- Erwig L-P, Henson PM. Clearance of apoptotic cells by phagocytes. Cell Death Differentiation. 2008;15:243–250.[CrossRef][Medline]
[Order article via Infotrieve]
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Related Article in Blood Online:
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Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4
- Ruby F. Fernandez-Boyanapalli, S. Courtney Frasch, Kathleen McPhillips, R. William Vandivier, Brian L. Harry, David W. H. Riches, Peter M. Henson, and Donna L. Bratton
Blood 2009 113: 2047-2055.
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