Absence of Formyl Peptide Receptor (FPR)-1 improves the outcome in mouse models of acute and chronic inflammation

Formyl peptide receptors (FPRs) are a family of G protein-coupled receptors, whose principal function is to detect the presence of pathogen-associated molecules or harmful endogenous ligands, including also typical biomarkers of immune activation and inflammation. In humans, the FPR family is constituted by FPR1, FPR2, and FPR3, all three functional receptors encoded by three genes, while in rodents, three genes encode functional receptors and six genes encode orphan receptors. In particular, FPR1 was the first neutrophil chemoattractant receptor to be characterized biochemically and has been shown to be a key player in innate immunity and host defence. FPR1 can trigger several signaling pathways for immune reactions during inflammation. In particular, once the receptor is activated, neutrophils migrate toward the site of injury, initiating the inflammatory response by releasing a number of proinflammatory mediators, thus amplifying the immune response. Formyl peptides bind to FPRs on neutrophils, activate Gi proteins, and induce the G-α subunit to dissociate from the G-βγ subunits. Gβγ subunits mediate downstream responses such as calcium influx, PI3K, PLC, Akt and MAPK. The phosphorylation of ERK, JNK, and p38 MAPK mediate FPR1-mediated transcriptional activity and chemotaxis, and it promotes a chemokine/chemoattractant-triggered function as a pro-inflammatory response. Upon the activation of these signals, neutrophils respond with chemotaxis, migration, translocation, phagocytosis, respiratory burst, and degranulation. Moreover, activation of FPR1 has been shown to trigger activation of the NF-kB pathway. NF-kB is a chief regulator of inflammation, it controlling various cellular processes such as apoptosis, cell proliferation, the secretion of cytokines, and oxidative stress. Additionally, NF-kB activates the transcription of target genes involved in the enhancement of the inflammatory process, including the NLRP3 inflammasome, a cytosolic protein complex. This complex contains NLRP3, a NOD-like receptor that is a sensor for inflammasome activation, and an apoptosis-associated speck-like protein containing a CARD complex (ASC), through which it binds pro-caspase. Pro-caspase, in turn, is cleaved in caspase-1 (Casp-1), which is a protease involved in apoptosis. It also controls the inflammatory response by release of cytokines. Indeed, Casp-1 is responsible of cleavage of pro-interleukin (IL)-1β and pro-IL-18 into the respective active cytokines. Both cytokines induces signal transduction cascades in inflammatory pathways in several cell types. The therapeutic potential of FPRs modulation has been confirmed in experimental models of acute or chronic inflammatory diseases, such as colitis and endometriosis. In light of the above, we investigated the effects of Fpr-1 deletion in two different models of inflammation in vivo: BOS in chronic and TBI in acute and chronic. Considering that BOS is a disease of inflammatory nature, we performed an experimental study to explore the molecular and cellular processes involved in airway repair and regeneration through FPR and NLRP3 pathways. Additionally, several studies have found that FPR1 was expressed in neurons. In this regard, in the second study, we decide to investigate the effect of genetic deficiency of Fpr-1 in mice subjected to TBI from the early stage of acute inflammation to neurogenesis 4 weeks after injury. Therefore, targeting FPRs has strong potential, and once supported by a greater knowledge of the functional role of FPR receptors, may bring about novel options in treatment of acute and chronic inflammation.