Excretory/Secretory Products From Trichinella spiralis Adult Worms Attenuated DSS-Induced Colitis in Mice by Driving PD-1-Mediated M2 Macrophage Polarization

Front Immunol. 2020 Oct 2;11:563784. doi: 10.3389/fimmu.2020.563784. eCollection 2020.

Abstract

Helminth-modulated macrophages contribute to attenuating inflammation in inflammatory bowel diseases. The programmed death 1 (PD-1) plays an important role in macrophage polarization and is essential in the maintenance of immune system homeostasis. Here, we investigate the role of PD-1-mediated polarization of M2 macrophages and the protective effects of excretory/secretory products from Trichinella spiralis adult worms (AES) on DSS-induced colitis in mice. Colitis in mice was induced by oral administration of dextran sodium sulfate (DSS) daily. Mice with DSS-induced colitis were treated with T. spiralis AES intraperitoneally, and pathological manifestations were evaluated. Macrophages in mice were depleted with liposomal clodronate. Markers for M1-type (iNOS, TNF-α) and M2-type (CD206, Arg-1) macrophages were detected by qRT-PCR and flow cytometry. Macrophage expression of PD-1 was quantified by flow cytometry; RAW 264.7 cells and peritoneal macrophages were used for in vitro tests, and PD-1 gene knockout mice were used for in vivo investigation of the role of PD-1 in AES-induced M2 macrophage polarization. Macrophage depletion was found to reduce DSS-induced colitis in mice. Treatment with T. spiralis AES significantly increased macrophage expression of CD206 and Arg-1 and simultaneously attenuated colitis severity. We found T. spiralis AES to enhance M2 macrophage polarization; these findings were confirmed studying in vitro cultures of RAW264.7 cells and peritoneal macrophages from mice. Further experimentation revealed that AES upregulated PD-1 expression, primarily on M2 macrophages expressing CD206. The AES-induced M2 polarization was found to be decreased in PD-1 deficient macrophages, and the therapeutic effects of AES on colitis was reduced in PD-1 knockout mice. In conclusion, the protective effects of T. spiralis AES on DSS-induced colitis were found to associate with PD-1 upregulation and M2 macrophage polarization. Thus, PD-1-mediated M2 macrophage polarization is a key mechanism of helminth-induced modulation of the host immune system.

Keywords: Trichinella spiralis; excretory/secretory products; inflammatory bowel disease; macrophages; programmed death 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bodily Secretions*
  • Cell Polarity / genetics*
  • Colitis / chemically induced*
  • Colitis / immunology
  • Colitis / therapy*
  • Dextran Sulfate / adverse effects*
  • Disease Models, Animal
  • Female
  • Gene Knockout Techniques
  • Macrophage Activation
  • Macrophages, Peritoneal / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism*
  • RAW 264.7 Cells
  • Rats
  • Trichinella spiralis / metabolism*

Substances

  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Dextran Sulfate