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  • Fpr appears to be an indispensable component of

    2021-11-26

    Fpr2 appears to be an indispensable component of the signaling chain governing dendritic cell trafficking in allergic airway inflammation (Chen et al., 2010). The FPR3 agonist FL2 is chemoattractant for dendritic cells, but its biological role in vivo is yet to be defined. Within the inflammatory site, FPR signaling has been reported to regulate survival and clearance of infiltrating cells. For instance, SAA and LL-37 delays (El Kebir et al., 2007, Wan et al., 2011), whereas AnxA1 accelerates constitutive PMN apoptosis (Perretti and Solito, 2004), a critical checkpoint for the resolution of inflammation (Rossi et al., 2006, El Kebir and Filep, 2013). LXA4 or 15-epi-LXA4 alone did not affect PMN apoptosis (József et al., 2002), whereas they overrode the potent anti-apoptosis signal from SAA (El Kebir et al., 2007). By contrast, in COPD patients, SAA produced within the lung opposes LXA4 and contributes to glucocorticoid refractory inflammation (Bozinovski et al., 2012). The FPR family plays a pivotal role in regulating the phagocytic activity of macrophages. Macrophage phagocytosis of apoptotic cells, or efferocytosis, assures safe resolution and avoids autoantigen exposure and metabolic stress (Elliott and Ravichandran, 2016). Efferocytic macrophages release IL-10 and TGF β that drive tissue repair and resolution (Bosurgi et al., 2017). A unique subset of pro-resolving macrophages, satiated macrophages, is generated during resolving inflammation (Schif-Zuck et al., 2011, Sugimoto et al., 2017) and express 12/15-lipoxygenase (LOX), an enzyme involved in the synthesis of SPMs (Serhan, 2014). This may represent a self-amplifying loop for accelerating resolution, for LXA4, RvD1, and AnxA1through FPR2/LXA stimulate efferocytosis (Mitchell et al., 2002, Perretti and D`Acquisto, 2009). Fibroblasts express all 3 FPRs and signaling through yet undefined FPRs has been proposed converting self-limited regenerative repair into an aberrant fibrotic process, an important feature of many chronic diseases, including myocardial infarction, idiopathic pulmonary fibrosis and systemic sclerosis (Rossi et al., 2015).
    Ligand-biased FPR signaling Studies with receptor chimeras and site-directed mutaganesis aided by computer modelling identified multiple charged Caspase-6 Colorimetric Assay Kit in transmembrane portions TM2 and TM7 that are essential for the high affinity binding of fMLF to FPR1, whereas other residues seem to be required for the interaction with FPR2/ALX (He and Ye, 2017). The binding pocket of FPR2/ALX is larger and deeper than that in FPR1, thereby capable of accommodating larger peptides. Peptide and lipid ligands act with different affinities and bind to distinct pockets on the receptor, thus making direct competition unlikely (Ye et al., 2009). Indeed, the 7th trans-membrane domain and adjacent regions of FPR2/ALX are essential for recognition of LXA4, whereas other regions, including the N-terminal domain or first two extracellular loops, are required for high-affinity binding of proteins (Chiang et al., 2000, Bena et al., 2012). Clearly, additional docking studies are needed to explore further the structure-function relationship of FPRs before crystal structures become available. At present, little is known about the molecular basis for how FPRs respond to different ligands and integrate opposing cues that triggers diverse biological responses. Ligation of FPR2/ALX triggers multiple downstream signaling pathways, resulting in the induction of a variety of function. For instance, PMN migration requires activation of PI-3K, Rac2, PTEN (phosphatase and tensin homologue deleted on chromosome 10) and p38 MAPK, whereas superoxide generation by NADPH oxidase requires Rac, PKC, Akt, ERK and p38 MAPK (Mayadas et al., 2014). SAA evokes NF-κB activation to regulate IL-8 gene transcription (He et al., 2003). LXA4 exerts atypical agonistic activities at FPR2/ALX, as it induces accumulation of presqualene diphosphate, leading to inhibition of NADPH oxidase (Levy et al., 1999) and NF-κB activation (József et al., 2002). Of note, activation of signaling pathways appears to be cell type-dependent. For example, recent studies indicate that LXA4 and 15-epi-LXA4 trigger expression of suppressor of cytokine signaling (SOCS-2) through activation of the aryl hydrocarbon receptor and FPR2/ALX in dendritic cells (Machado et al., 2006) and stimulates ERK2 phosphorylation to activate primary monocytes in a non-phlogistic manner (Cooray et al., 2013). SPM signaling can promote expression of agonists for FPRs, exemplified by AnxA1 or RvE1 signaling promoting increased synthesis of LXA4 (Perretti et al., 2002, Haworth et al., 2008), leading to a positive feed forward resolution circuit.