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

Devitt A, Parker KG, Ogden CA, Oldreive C, Clay MF, Melville LA, Bellamy CO, Lacy-Hulbert A, Gangloff SC, Goyert SM, Gregory CD - J. Cell Biol. (2004)

Bottom Line: Significantly, CD14(-/-) macrophages in vivo are defective in clearing apoptotic cells in multiple tissues, suggesting a broad role for CD14 in the clearance process.However, the resultant persistence of apoptotic cells does not lead to inflammation or increased autoantibody production, most likely because, as we show, CD14(-/-) macrophages retain the ability to generate anti-inflammatory signals in response to apoptotic cells.We conclude that CD14 plays a broad tethering role in apoptotic cell clearance in vivo and that apoptotic cells can persist in the absence of proinflammatory consequences.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.

ABSTRACT
Interaction of macrophages with apoptotic cells involves multiple steps including recognition, tethering, phagocytosis, and anti-inflammatory macrophage responses. Defective apoptotic cell clearance is associated with pathogenesis of autoimmune disease. CD14 is a surface receptor that functions in vitro in the removal of apoptotic cells by human and murine macrophages, but its mechanism of action has not been defined. Here, we demonstrate that CD14 functions as a macrophage tethering receptor for apoptotic cells. Significantly, CD14(-/-) macrophages in vivo are defective in clearing apoptotic cells in multiple tissues, suggesting a broad role for CD14 in the clearance process. However, the resultant persistence of apoptotic cells does not lead to inflammation or increased autoantibody production, most likely because, as we show, CD14(-/-) macrophages retain the ability to generate anti-inflammatory signals in response to apoptotic cells. We conclude that CD14 plays a broad tethering role in apoptotic cell clearance in vivo and that apoptotic cells can persist in the absence of proinflammatory consequences.

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Persistence of apoptotic cells in CD14−/− mice does not lead to increased autoantibody production or inflammation. (A) Autoantibody production is not increased in CD14−/− mice. Titers of ANA antibodies in sera from aged CD14−/− and CD14+/+ mice were assessed by indirect immunofluorescence. See text for details. “−” denotes negative samples. (B) CD14−/− macrophages produce TGF-β effectively in response to apoptotic cells. TGF-β concentration in the supernatants of peritoneal macrophages following 18-h stimulation alone or with apoptotic thymocytes (AC). Data shown are means ± SEM, n = 5. ANOVA: ***, P < 0.001. (C) Apoptotic cells can inhibit proinflammatory responses of CD14-deficient macrophages. (left) TNF-α concentration in the supernatants of 10-d BMDMs following 18-h stimulation with both or either opsonized zymosan (Zy) and apoptotic thymocytes (AC). Data shown are means ± SEM, n = 3. ANOVA: ***, P < 0.001.
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fig6: Persistence of apoptotic cells in CD14−/− mice does not lead to increased autoantibody production or inflammation. (A) Autoantibody production is not increased in CD14−/− mice. Titers of ANA antibodies in sera from aged CD14−/− and CD14+/+ mice were assessed by indirect immunofluorescence. See text for details. “−” denotes negative samples. (B) CD14−/− macrophages produce TGF-β effectively in response to apoptotic cells. TGF-β concentration in the supernatants of peritoneal macrophages following 18-h stimulation alone or with apoptotic thymocytes (AC). Data shown are means ± SEM, n = 5. ANOVA: ***, P < 0.001. (C) Apoptotic cells can inhibit proinflammatory responses of CD14-deficient macrophages. (left) TNF-α concentration in the supernatants of 10-d BMDMs following 18-h stimulation with both or either opsonized zymosan (Zy) and apoptotic thymocytes (AC). Data shown are means ± SEM, n = 3. ANOVA: ***, P < 0.001.

Mentions: Persistence of apoptotic cells in vivo was expected to be associated with inflammation and increased autoantibody production. However, CD14−/− mice showed no overt inflammatory lesions (Fig. 3 H and not depicted) or increased serum concentration of TNF-α (not depicted) despite the chronic presence of apoptotic cells within tissues. We also monitored autoantibody titers and autoimmune disease pathology in aged animals and found titers of anti-nuclear antibodies (ANA) were comparable in sera of CD14+/+ and CD14−/− animals (Fig. 6 A). Extensive histopathological analyses of tissues from these animals (unpublished data) indicated no end organ effects. Thus, in these animals, persistence of apoptotic cells resulting from the absence of CD14 does not augment autoantibody production or lead to increased susceptibility to autoimmune disease.


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

Devitt A, Parker KG, Ogden CA, Oldreive C, Clay MF, Melville LA, Bellamy CO, Lacy-Hulbert A, Gangloff SC, Goyert SM, Gregory CD - J. Cell Biol. (2004)

Persistence of apoptotic cells in CD14−/− mice does not lead to increased autoantibody production or inflammation. (A) Autoantibody production is not increased in CD14−/− mice. Titers of ANA antibodies in sera from aged CD14−/− and CD14+/+ mice were assessed by indirect immunofluorescence. See text for details. “−” denotes negative samples. (B) CD14−/− macrophages produce TGF-β effectively in response to apoptotic cells. TGF-β concentration in the supernatants of peritoneal macrophages following 18-h stimulation alone or with apoptotic thymocytes (AC). Data shown are means ± SEM, n = 5. ANOVA: ***, P < 0.001. (C) Apoptotic cells can inhibit proinflammatory responses of CD14-deficient macrophages. (left) TNF-α concentration in the supernatants of 10-d BMDMs following 18-h stimulation with both or either opsonized zymosan (Zy) and apoptotic thymocytes (AC). Data shown are means ± SEM, n = 3. ANOVA: ***, P < 0.001.
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fig6: Persistence of apoptotic cells in CD14−/− mice does not lead to increased autoantibody production or inflammation. (A) Autoantibody production is not increased in CD14−/− mice. Titers of ANA antibodies in sera from aged CD14−/− and CD14+/+ mice were assessed by indirect immunofluorescence. See text for details. “−” denotes negative samples. (B) CD14−/− macrophages produce TGF-β effectively in response to apoptotic cells. TGF-β concentration in the supernatants of peritoneal macrophages following 18-h stimulation alone or with apoptotic thymocytes (AC). Data shown are means ± SEM, n = 5. ANOVA: ***, P < 0.001. (C) Apoptotic cells can inhibit proinflammatory responses of CD14-deficient macrophages. (left) TNF-α concentration in the supernatants of 10-d BMDMs following 18-h stimulation with both or either opsonized zymosan (Zy) and apoptotic thymocytes (AC). Data shown are means ± SEM, n = 3. ANOVA: ***, P < 0.001.
Mentions: Persistence of apoptotic cells in vivo was expected to be associated with inflammation and increased autoantibody production. However, CD14−/− mice showed no overt inflammatory lesions (Fig. 3 H and not depicted) or increased serum concentration of TNF-α (not depicted) despite the chronic presence of apoptotic cells within tissues. We also monitored autoantibody titers and autoimmune disease pathology in aged animals and found titers of anti-nuclear antibodies (ANA) were comparable in sera of CD14+/+ and CD14−/− animals (Fig. 6 A). Extensive histopathological analyses of tissues from these animals (unpublished data) indicated no end organ effects. Thus, in these animals, persistence of apoptotic cells resulting from the absence of CD14 does not augment autoantibody production or lead to increased susceptibility to autoimmune disease.

Bottom Line: Significantly, CD14(-/-) macrophages in vivo are defective in clearing apoptotic cells in multiple tissues, suggesting a broad role for CD14 in the clearance process.However, the resultant persistence of apoptotic cells does not lead to inflammation or increased autoantibody production, most likely because, as we show, CD14(-/-) macrophages retain the ability to generate anti-inflammatory signals in response to apoptotic cells.We conclude that CD14 plays a broad tethering role in apoptotic cell clearance in vivo and that apoptotic cells can persist in the absence of proinflammatory consequences.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.

ABSTRACT
Interaction of macrophages with apoptotic cells involves multiple steps including recognition, tethering, phagocytosis, and anti-inflammatory macrophage responses. Defective apoptotic cell clearance is associated with pathogenesis of autoimmune disease. CD14 is a surface receptor that functions in vitro in the removal of apoptotic cells by human and murine macrophages, but its mechanism of action has not been defined. Here, we demonstrate that CD14 functions as a macrophage tethering receptor for apoptotic cells. Significantly, CD14(-/-) macrophages in vivo are defective in clearing apoptotic cells in multiple tissues, suggesting a broad role for CD14 in the clearance process. However, the resultant persistence of apoptotic cells does not lead to inflammation or increased autoantibody production, most likely because, as we show, CD14(-/-) macrophages retain the ability to generate anti-inflammatory signals in response to apoptotic cells. We conclude that CD14 plays a broad tethering role in apoptotic cell clearance in vivo and that apoptotic cells can persist in the absence of proinflammatory consequences.

Show MeSH
Related in: MedlinePlus