The role of autophagy in asparaginase-induced immune suppression of macrophages

Cell Death Dis. 2017 Mar 30;8(3):e2721. doi: 10.1038/cddis.2017.144.

Abstract

Erwinia asparaginase, a bacteria-derived enzyme drug, has been used in the treatment of various cancers, especially acute lymphoblastic leukemia (ALL). One of the most significant side effects associated with asparaginase administration is immune suppression, which limits its application in clinic. Macrophages are phagocytic immune cells and have a central role in inflammation and host defense. We reported here that asparaginase disturbed the function of macrophages including phagocytosis, proliferation, ROS and nitric oxide secretion, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) secretion, and major histocompatibility complex II (MHC-II) molecule expression, thus induced immune suppression in interferon-γ and lipopolysaccharide-stimulated macrophages. We also observed that asparaginase inhibited autophagy in macrophages via activating Akt/mTOR and suppressing Erk1/2 signaling pathway as evidenced by less formation of autophagosomes, downregulation of autophagy-related protein LC3-II, and decreased number of autophagy-like vacuoles. Further study discovered that treatment with autophagy inhibitor 3-MA in place of asparaginase on activated macrophages could also downregulate phagocytosis, cytokine secretion, and MHC-II expression. Moreover, incubation with autophagy inducer trehalose restored the capacity of phagocytosis, IL-6 and TNF-α secretion, and MHC-II expression in macrophages. These results prove the important role of autophagy in the function of macrophages, and activation of autophagy can overcome asparaginase-induced immune suppression in macrophages.

MeSH terms

  • Animals
  • Asparaginase / pharmacology*
  • Autophagy / drug effects*
  • Bacterial Proteins / pharmacology*
  • Cells, Cultured
  • Erwinia / enzymology
  • Immunosuppressive Agents / pharmacology*
  • Interleukin-6 / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Macrophages, Peritoneal / metabolism*
  • Male
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Bacterial Proteins
  • IL6 protein, human
  • Immunosuppressive Agents
  • Interleukin-6
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Asparaginase