CD13/aminopeptidase N Is a Negative Regulator of Mast Cell Activation

FASEB J. 2016 Jun;30(6):2225-35. doi: 10.1096/fj.201600278. Epub 2016 Mar 2.

Abstract

Antigen-induced mast cell (MC) activation via cross-linking of IgE-bound high-affinity receptors for IgE (FcεRI) underlies type I allergy and anaphylactic shock. Comprehensive knowledge of FcεRI regulation is thus required. We have identified a functional interaction between FcεRI and CD13 in murine MCs. Antigen-triggered activation of IgE-loaded FcεRI results in cocapping and cointernalization of CD13 and equivalent internalization rates of up to 40%. Cointernalization is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internalization. Moreover, antibody-mediated cross-linking of CD13 causes IL-6 production in an FcεRI-dependent manner. These data are indicative of a functional interaction between FcεRI and CD13 on MCs. To determine the role of this interaction, CD13-deficient bone marrow-derived MCs (BMMCs) were analyzed. Intriguingly, antigen stimulation of CD13-deficient BMMCs results in significantly increased degranulation and proinflammatory cytokine production compared to wild-type cells. Furthermore, in a low-dose model of passive systemic anaphylaxis, antigen-dependent decrease in body temperature, reflecting the anaphylactic reaction, is substantially enhanced by the CD13 inhibitor bestatin (-5.9 ± 0.6°C) and by CD13 deficiency (-8.8 ± 0.6°C) in contrast to controls (-1.2 ± 1.97°C). Importantly, bestatin does not aggravate anaphylaxis in CD13-deficient mice. Thus, we have identified CD13 as a novel negative regulator of MC activation in vitro and in vivo-Zotz, J. S., Wölbing, F., Lassnig, C., Kauffmann, M., Schulte, U., Kolb, A., Whitelaw, B., Müller, M., Biedermann, T., Huber, M. CD13/aminopeptidase N is a negative regulator of mast cell activation.

Keywords: IgE receptor; degranulation; passive systemic anaphylaxis; proinflammatory cytokines; receptor internalization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphylaxis
  • Animals
  • CD13 Antigens / antagonists & inhibitors
  • CD13 Antigens / genetics
  • CD13 Antigens / metabolism*
  • Cell Proliferation
  • Dinitrophenols / immunology
  • Gene Expression Regulation / physiology
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Macrophages
  • Mast Cells / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, IgE / genetics
  • Receptors, IgE / metabolism
  • Serum Albumin / immunology

Substances

  • Dinitrophenols
  • Receptors, IgE
  • Serum Albumin
  • dinitrophenyl-human serum albumin conjugate
  • CD13 Antigens
  • Leucine
  • ubenimex