In recent years many studies have demonstrated that the
In recent years, many studies have demonstrated that the release of endogenous FPR ligands can influence severe diseases associated with inflammation, including systemic inflammatory response syndrome (SIRS)20, 21 and cancers, such as glioblastoma as well as gastric and colorectal cancer 22, 23, 24. Indeed, tumoral FPRs frequently serve to support cancer proliferation and metastasis 22, 23, 24. Moreover, heightened FPR expression in tumor cells often correlates with poor prognosis relative to low FPR1 expressing tumors . However, this is only one side of the coin. In addition, effective chemotherapy-induced antitumor responses against breast cancer have been reported to require functional FPR1 expression, since breast cancer patients who bear loss-of-function Trelagliptin in FPR1 exhibit reduced survival after treatment with adjuvant chemotherapy 26, 27. As all bacteria (and many pathogens) release FPR ligands and some even FPR inhibitors [such as the chemotaxis-inhibitory protein of Staphylococcus aureus (CHIPS) and FPR2-inhibitory protein (FLIPr); Box 2], it is therefore crucial to clarify the role of FPRs in infection as well as in inflammatory processes. Here, we review recent findings concerning the role of FPRs in disease. We provide an overview on the consequences of FPR expression and activation in the context of bacterial and viral infections as well as during inflammation and cancer. Since FPRs are involved in such diverse processes, to our knowledge, we try to connect for the first time the role of FPRs in these various scientific fields. It will be necessary to further interrelate these research topics in the future to better understand the mechanistic roles of these pathways in health and disease.
Sensing Invading Bacterial Pathogens via FPRs
Role of FPRs in Viral Infections
Role of FPRs during Sterile Inflammation FPRs seem to be critical for normal healing of a sterile wound, since they can mediate the first wave of neutrophil infiltration . Specifically, during sterile inflammation, neutrophil recruitment is mediated by the release of damage-associated molecular patterns (DAMPs) following the rupture of the plasma membrane 57, 58. Neutrophils migrate out of the circulatory system toward the site of injury, initiating the inflammatory response by releasing a number of proinflammatory mediators, thus amplifying the immune response . Mitochondrial peptides can induce inflammatory processes via FPR1- and FPR2-mediated activation of neutrophils (Figure 3A) . Specifically, in wild-type mice, neutrophils rapidly infiltrate the dermis of a sterile skin wound prior to the initiation of chemokine production by the injured tissue. By contrast, rapid neutrophil infiltration is markedly reduced and wound closure is delayed in mice globally deficient in both mFprs . From another angle, a detrimental effect of FPR-mediated inflammation can be observed in proliferative diabetic retinopathy (PDR), a major complication of diabetes mellitus. Using human pars plana vitrectomy-derived PDR vitreous fluid samples in murine Matrigel plug and chick embryo chorioallantoic membrane assays, FPR1-induced inflammation and neovessel formation have been shown to trigger PDR, which can eventually lead to blindness . Furthermore, traumatic injury can induce SIRS or a ‘cytokine storm’ . SIRS is characterized by the release of proinflammatory cytokines into the circulation, leading to marked immune cell activation. Formylated DAMPs released from necrotic cells due to tissue damage can initiate the SIRS response . During SIRS, neutrophils are recruited to distal organs where they can contribute to the development of multiple organ dysfunction, circulatory collapse, and potentially death . In general, FPR1 activation is deemed as a key event in mitochondrial DAMP-induced neutrophil activation . Moreover, formylated mitochondrial peptides can induce sepsis-like syndrome and cardiovascular collapse (Figure 3A) in rats undergoing hemorrhagic shock, with increased plasma concentrations of mitochondrial formylated proteins associated with lung damage, relative to rats treated with the FPR2 inhibitor WRW4 (Figure 3A) . Similar results have been observed in acute respiratory distress syndrome (ARDS): mitochondrial-derived formylated peptides (fMITs) were elevated in both bronchoalveolar lavage fluid and serum samples from patients with ARDS . In summary, these data suggest that formylated peptides may potentially link mechanisms of sterile inflammation in trauma, SIRS, and cardiovascular collapse. However, despite unwanted collateral damage induced by overwhelming neutrophil recruitment, the infiltration of neutrophils to a sterile site of injury may also play a significant role in prompting the resolution of inflammation and wound closure . Therefore, well-defined FPR activation and signaling are necessary to ensure an optimal immune response.