Exogenous IL-4 shuts off pro-inflammation in neutrophils while stimulating anti-inflammation in macrophages to induce neutrophil phagocytosis following myocardial infarction

Michael J. Daseke, Mavis A.A. Tenkorang-Impraim, Yonggang Ma, Upendra Chalise, Shelby R. Konfrst, Michael R. Garrett, Kristine Y. DeLeon-Pennell, Merry L. Lindsey

Research output: Contribution to journalArticle

Abstract

Introduction: Macrophages and neutrophils are primary leukocytes involved in the inflammatory response to myocardial infarction (MI). While interleukin (IL)-4 is an in vitro anti-inflammatory stimulus, the MI myocardium does not express a considerable amount of IL-4 but does express IL4 receptors. We hypothesized that continuous exogenous IL-4 infusion starting 24 h after MI would promote a polarization switch in inflammatory cells towards a reparative phenotype. Methods: C57BL/6J male mice (3–6 months of age) were subcutaneously infused with either saline (n = 17) or IL-4 (20 ng/g/day; n = 17) beginning 24 h after MI and evaluated at MI day 3. Results: Macrophages and neutrophils were isolated ex vivo from the infarct region and examined. Exogenous IL-4 decreased pro-inflammatory Ccl3, Il12a, Tnfa, and Tgfb1 in neutrophils and increased anti-inflammatory Arg1 and Ym1 in macrophages (all p <.05). Tissue clearance by IL-4 treated neutrophils was not different, while selective phagocytosis of neutrophils doubled in IL-4 treated macrophages (p <.05). Of 24,339 genes examined by RNA-sequencing, 2042 genes were differentially expressed in macrophages from IL-4 stimulated infarct (all FDR p <.05). Pdgfc gene expression was ranked first, increasing 3-fold in macrophages stimulated with IL-4 (p = 1 × 10−9). Importantly, changes in macrophage physiology and transcriptome occurred in the absence of global LV effects. Bone marrow derived monocytes stimulated with mouse recombinant PDGF-CC protein (10 μg/ml) or PDGF-CC blocking antibody (200 ng/ml) did not change Arg1 or Ym1 expression, indicating the in vivo effect of IL-4 to stimulate macrophage anti-inflammatory gene expression was independent of PDGF-CC. Conclusions: Our results indicate that exogenous IL-4 promotes inflammation resolution by turning off pro-inflammation in neutrophils while stimulating anti-inflammation in macrophages to mediate removal of apoptotic neutrophils.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume145
DOIs
StatePublished - Aug 2020

Keywords

  • Cardiac repair
  • IL-4
  • Inflammation
  • Macrophage
  • Myocardial infarction
  • Phagocytosis

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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