Modulation of NLRP3 Inflammasome through Formyl Peptide Receptor 1 (Fpr-1) Pathway as a New Therapeutic Target in Bronchiolitis Obliterans Syndrome

Int J Mol Sci. 2020 Mar 20;21(6):2144. doi: 10.3390/ijms21062144.

Abstract

Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Bronchiolitis obliterans syndrome (BOS), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. We investigated, using transgenic mice, the mechanisms through which the deficiency of IL-1β/IL-18, Casp-1, or Fpr-1 genes could be protective in an experimental model of BOS, induced in mice by allogeneic heterotopic tracheal transplantation. Fpr-1 KO mice showed a marked reduction in histological markers of BOS and of mast cell numbers compared to other groups. Molecular analyses indicated that the absence of the Fpr-1 gene was able to decrease NF-κB nuclear translocation and modulate NLRP3 inflammasome signaling and the mitogen-activated protein kinase (MAPK) pathway in a more significant way compared to other groups. Additionally, Fpr-1 gene deletion caused a reduction in resistance to the apoptosis, assessed by the TUNEL assay. Immunohistochemical analyses indicated changes in nitrotyrosine, PARP, VEGF, and TGF-β expression associated with the pathology, which were reduced in the absence of the Fpr1 gene more so than by the deletion of IL-1β/IL-18 and Casp-1. We underline the importance of the NLRP3 inflammasome and the pathogenic role of Fpr-1 in experimental models of BOS, which is the result of the modulation of immune cell recruitment together with the modulation of local cellular activation, suggesting this gene as a new target in the control of the pathologic features of BOS.

Keywords: bronchiolitis obliterans syndrome; inflammasome; inflammation.

MeSH terms

  • Animals
  • Apoptosis
  • Bronchiolitis Obliterans / drug therapy*
  • Caspase 1 / metabolism
  • Cell Count
  • Enzyme Activation
  • Inflammasomes / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Male
  • Mast Cells / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Targeted Therapy*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Receptors, Formyl Peptide / metabolism*
  • Signal Transduction*
  • Syndrome
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Inflammasomes
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Receptors, Formyl Peptide
  • 3-nitrotyrosine
  • Tyrosine
  • Nitric Oxide Synthase Type II
  • Poly(ADP-ribose) Polymerases
  • Mitogen-Activated Protein Kinases
  • Caspase 1