Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response

Michael Miksa, Dhruv Amin, Rongqian Wu, Asha Jacob, Mian Zhou, Weifeng Dong, Weng Lang Yang, Thanjavur S. Ravikumar, Ping Wang

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

In sepsis, phagocytosis and the killing of bacteria by phagocytes are important. Similarly, the clearance of accumulating apoptotic cells is critical in maintaining normal immunity. Upon maturation, peritoneal macrophages (PM) become a major source of proinflammatory cytokines, while losing their efficacy of phagocytosis. However, the underlying mechanism remains unknown. Here we investigated the differential effects of apoptotic thymocytes (AoTC) on TNF-a release in immature thioglycolate-elicited PM (TGPM) and mature resident PM (RPM) in vitro by culturing them with or without AoTC and/or LPS. MFG-E8 expression was assessed using Western blotting and the ability to engulf AoTC was determined histologically. Cytokine secretion was measured by ELISA. MAP kinase phosphorylation was assessed using Western blotting. Mature RPM express <50% of TGPM MFG-E8 levels and have a 30% lower capacity to clear AoTC. The proinflammatory response (TNF-α release) to LPS is 5 times higher, and the capability to phagocytose is decreased along with further down-regulation of MFG-E8 after LPS-stimulation. RPMs also lack phagocytosis-induced inhibition of TNF-α release after LPS stimulation. LPS-induced phosphorylation of ERK 1/2, p38 and JNK is more enhanced in RPM compared to TGPM. MFG-E8-mediated apoptotic cell phagocytosis results in an inhibition of MAPK and NFκB signaling pathways. Differential MAPK activation may play a role in the enhanced LPS responsiveness of RPM and the lack of MFG-E8 impedes post-phagocytic suppression of LPS-response through the inhibition of those signaling pathways. These results provide a potential mechanistic insight into the benefit of promoting apoptotic cell clearance via MFG-E8 under inflammatory conditions.

Original languageEnglish (US)
Pages (from-to)743-748
Number of pages6
JournalInternational Journal of Molecular Medicine
Volume22
Issue number6
DOIs
StatePublished - 2008
Externally publishedYes

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Thymocytes
Thioglycolates
Phagocytosis
Endotoxins
Peritoneal Macrophages
Down-Regulation
Western Blotting
Phosphorylation
Cytokines
Cytophagocytosis
Phagocytes
Immunity
Sepsis
Phosphotransferases
Enzyme-Linked Immunosorbent Assay
Bacteria

Keywords

  • Macrophages
  • Phagocytosis
  • TNF-α

ASJC Scopus subject areas

  • Genetics

Cite this

Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response. / Miksa, Michael; Amin, Dhruv; Wu, Rongqian; Jacob, Asha; Zhou, Mian; Dong, Weifeng; Yang, Weng Lang; Ravikumar, Thanjavur S.; Wang, Ping.

In: International Journal of Molecular Medicine, Vol. 22, No. 6, 2008, p. 743-748.

Research output: Contribution to journalArticle

Miksa, M, Amin, D, Wu, R, Jacob, A, Zhou, M, Dong, W, Yang, WL, Ravikumar, TS & Wang, P 2008, 'Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response', International Journal of Molecular Medicine, vol. 22, no. 6, pp. 743-748. https://doi.org/10.3892/ijmm_00000080
Miksa, Michael ; Amin, Dhruv ; Wu, Rongqian ; Jacob, Asha ; Zhou, Mian ; Dong, Weifeng ; Yang, Weng Lang ; Ravikumar, Thanjavur S. ; Wang, Ping. / Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response. In: International Journal of Molecular Medicine. 2008 ; Vol. 22, No. 6. pp. 743-748.
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AU - Amin, Dhruv

AU - Wu, Rongqian

AU - Jacob, Asha

AU - Zhou, Mian

AU - Dong, Weifeng

AU - Yang, Weng Lang

AU - Ravikumar, Thanjavur S.

AU - Wang, Ping

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AB - In sepsis, phagocytosis and the killing of bacteria by phagocytes are important. Similarly, the clearance of accumulating apoptotic cells is critical in maintaining normal immunity. Upon maturation, peritoneal macrophages (PM) become a major source of proinflammatory cytokines, while losing their efficacy of phagocytosis. However, the underlying mechanism remains unknown. Here we investigated the differential effects of apoptotic thymocytes (AoTC) on TNF-a release in immature thioglycolate-elicited PM (TGPM) and mature resident PM (RPM) in vitro by culturing them with or without AoTC and/or LPS. MFG-E8 expression was assessed using Western blotting and the ability to engulf AoTC was determined histologically. Cytokine secretion was measured by ELISA. MAP kinase phosphorylation was assessed using Western blotting. Mature RPM express <50% of TGPM MFG-E8 levels and have a 30% lower capacity to clear AoTC. The proinflammatory response (TNF-α release) to LPS is 5 times higher, and the capability to phagocytose is decreased along with further down-regulation of MFG-E8 after LPS-stimulation. RPMs also lack phagocytosis-induced inhibition of TNF-α release after LPS stimulation. LPS-induced phosphorylation of ERK 1/2, p38 and JNK is more enhanced in RPM compared to TGPM. MFG-E8-mediated apoptotic cell phagocytosis results in an inhibition of MAPK and NFκB signaling pathways. Differential MAPK activation may play a role in the enhanced LPS responsiveness of RPM and the lack of MFG-E8 impedes post-phagocytic suppression of LPS-response through the inhibition of those signaling pathways. These results provide a potential mechanistic insight into the benefit of promoting apoptotic cell clearance via MFG-E8 under inflammatory conditions.

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