Acute Inflammation Primes Myeloid Effector Cells for Anti-Inflammatory STAT6 Signaling

Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13487-91. doi: 10.1073/pnas.1312525110. Epub 2013 Jul 29.

Abstract

The anti-inflammatory drug high-dose intravenous immunoglobulin, widely used to suppress inflammation, depends on a specific α-2,6-sialylated glycoform of IgG Fc to induce Interleukin 4 (IL-4) and Signal Transducer and Activator of Transcription 6 (STAT6) signaling for its activity. Here we show that anti-inflammatory activities of IL-4 can be attributed to the direct action of this cytokine on myeloid effector cells, depending on their expression of the IL-4 receptor alpha chain (IL-4Rα/CD124). However, in their basal state, these cells express low levels of IL-4Rα and would not be expected to result in significant signaling compared with other cell populations. This apparent paradox can be explained by the observation that during inflammation, triggered by a variety of stimuli (including autoantibodies, adjuvants, and TLR ligands), IL-4Rα is up-regulated specifically on these cells, priming them for STAT6 signaling. The regulation is mediated by a soluble, proteinase K-sensitive factor, released to the circulation by bone marrow-derived, non-B/non-T cells found in several organs, including the lungs, and fat. We propose that this regulation is part of a homeostatic mechanism to limit excessive inflammation and tissue damage. High-dose intravenous immunoglobulin thus exploits an endogenous feedback loop, general to inflammation, that could be further targeted for therapeutic purposes.

Keywords: macrophages; monocytes; neutrophils.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carpal Joints / immunology
  • Flow Cytometry
  • Gene Expression Regulation / immunology*
  • Histological Techniques
  • Homeostasis / immunology*
  • Immunoglobulins, Intravenous / metabolism
  • Immunoglobulins, Intravenous / pharmacology*
  • Inflammation / drug therapy
  • Inflammation / immunology*
  • Mice
  • Mice, Knockout
  • Myeloid Cells
  • Polymerase Chain Reaction
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, IgG / metabolism
  • STAT6 Transcription Factor / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Statistics, Nonparametric

Substances

  • Fcgr1 protein, mouse
  • Il4ra protein, mouse
  • Immunoglobulins, Intravenous
  • Receptors, Cell Surface
  • Receptors, IgG
  • STAT6 Transcription Factor