Research on molecular mechanisms of engulfment of apoptotic cells

Research output: Contribution to journalReview article

Abstract

Apoptotic cells generated during development and immune responses in animals are rapidly engulfed by phagocytes, such as macrophages and dendritic cells. When the engulfment process malfunctions, the apoptotic cells undergo secondary necrosis, which results in the release of noxious cellular components into the extracellular space. Thus, the effcient clearance of apoptotic cells is indispensable for the maintenance of tissue homeostasis; however, the molecular mechanisms underlying the engulfment of apoptotic cells remain largely unknown. To identify the molecules that are involved in this process, we developed a functional screening strategy using a retrovirus cDNA library. Using this assay, we isolated cDNA clones encoding RhoG and Rab5 which enhanced the engulfment of apoptotic cells. In addition, we found that Rac1, which is very similar to RhoG, and Rab5 are necessary for engulfment; their activities were successfully visualized by a combination of fluorescence resonance energy transfer technology with time-lapse imaging techniques. We further determined that G protein-coupled receptor kinase 6 (GRK6), originally identified as a kinase responsible for the desensitization and downregulation of G-protein-coupled receptors, activates Rac1 independent of the two known intracellular engulfment pathways in phagocytes. GRK6-deficient macrophages exhibited impaired phagocytosis of apoptotic cells. Consequently, GRK6-deficient mice developed autoimmune phenotypes such as an increase in the amount of anti-dsDNA in serum and the deposition of immune complexes in the kidney. Thus, our findings contributed to the understanding of the molecular mechanisms that regulate apoptotic engulfment in phagocytes.

Original languageEnglish
Pages (from-to)949-954
Number of pages6
JournalYakugaku Zasshi
Volume135
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

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Phagocytes
Research
Macrophages
Time-Lapse Imaging
Cytophagocytosis
Fluorescence Resonance Energy Transfer
Extracellular Space
Retroviridae
G-Protein-Coupled Receptors
Antigen-Antibody Complex
Gene Library
Dendritic Cells
Homeostasis
Necrosis
Phosphotransferases
Down-Regulation
Complementary DNA
Clone Cells
Maintenance
Technology

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Research on molecular mechanisms of engulfment of apoptotic cells. / Nakaya, Michio.

In: Yakugaku Zasshi, Vol. 135, No. 8, 01.08.2015, p. 949-954.

Research output: Contribution to journalReview article

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