CXCR4-CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice

Eur J Immunol. 2018 Jun;48(6):1020-1029. doi: 10.1002/eji.201747023. Epub 2018 Mar 23.

Abstract

Antibody-secreting cells (ASCs), including short-lived plasmablasts and long-lived memory plasma cells (LLPCs), contribute to autoimmune pathology. ASCs, particularly LLPCs, refractory to conventional immunosuppressive drugs pose a major therapeutic challenge. Since stromal cells expressing C-X-C motif chemokine-12 (CXCL12) organize survival niches for LLPCs in the bone marrow, we investigated the effects of CXCL12 and its ligand CXCR4 (C-X-C chemokine receptor 4) on ASCs in lupus mice (NZB/W). Fewer adoptively transferred splenic ASCs were retrieved from the bone marrow of recipient immunodeficient Rag1-/- mice when the ASCs were pretreated with the CXCR4 blocker AMD3100. CXCR4 blockade also significantly reduced anti-OVA ASCs in the bone marrow after secondary immunization with OVA. In this study, AMD3100 efficiently depleted ASCs, including LLPCs. After two weeks, it decreased the total number of ASCs in the spleen and bone marrow by more than 60%. Combination with the proteasome inhibitor bortezomib significantly enhanced the depletion effect of AMD3100. Continuous long-term (five-month) CXCR4 blockade with AMD3100 after effective short-term LLPCs depletion kept the number of LLPCs in the bone marrow low, delayed proteinuria development and prolonged the survival of the mice. These findings identify the CXCR4-CXCL12 axis as a potential therapeutic target likely due to its importance for ASC homing and survival.

Keywords: AMD3100; Antibody-secreting cells; Bortezomib; CXCR4-CXCL12 axis; NZB/W F1 mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation
  • Benzylamines
  • Bone Marrow / physiology*
  • Bortezomib / administration & dosage
  • Cell Movement
  • Cell Survival
  • Chemokine CXCL12 / metabolism*
  • Cyclams
  • Female
  • Heterocyclic Compounds / administration & dosage
  • Humans
  • Immunologic Memory
  • Lupus Nephritis / immunology
  • Lymphocyte Depletion
  • Lymphocyte Subsets / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NZB
  • Mice, Transgenic
  • Plasma Cells / physiology*
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / metabolism*

Substances

  • Benzylamines
  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cyclams
  • Heterocyclic Compounds
  • Receptors, CXCR4
  • Bortezomib
  • plerixafor