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

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.

Loganin Attenuates High Glucose-Induced Schwann Cells Pyroptosis by Inhibiting ROS Generation and NLRP3 Inflammasome Activation

“…Some chronic inflammatory conditions, such as endometriosis, bronchiolitis obliterans syndrome, etc. have been shown to regulate NLRP3 inflammasome via the Formyl Peptide Receptor 1 (Fpr-1)-mediated signaling pathway [ 16 , 17 ]. Many types of inflammasomes exist in various cell types.…”

“…The NLRP3 inflammasome is composed of the sensor molecule NLRP3, the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) and pro-caspase-1. The activation of NLRP3 inflammasomes is strictly regulated to avoid excessive inflammatory responses [ 17 , 19 ]. NLRP3 inflammasome activation requires a two-step process, a priming step and an activation step.…”

All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage

“…Additionally, NLRP3 inflammasome-derived IL-1β is also the major driver of chronic low-grade sterile inflammation that accompanies conditions, such as metabolic syndromes and aging, endometriosis, and bronchiolitis obliterans syndrome, eventually leading to tissue damage [2][3][4][5]. For this reason, the pharmacological manipulation of NLRP3 inflammasome has become the focus of intensive studies and medical trials [6][7][8].…”

Formyl peptide receptors in the mucosal immune system

“…In a murine BOS model, Fpr1 knockout mice showed attenuation of disease severity with decreased NF-κB nuclear translocation, MAPK signaling, and modulation of the NLRP3 inflammasome. The levels of cytokines directly related to fibrosis, such as VEGF and TGF-β, were also decreased in the Fpr1 knockout BOS mouse model 50 . These results suggest that FPR1 is detrimental in fibrotic diseases.…”