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    • Studies have indicated that formylated peptides FPRs

    2022-05-09

    Studies have indicated that formylated peptides, FPRs, and in particular FPR-1 may be principal conductors in inflammatory processes in sterile-24, 26 and infection-related diseases. FPR-1 and formylated peptides, which are active components of CS, have been involved in smoking-induced lung damage, and studies performed in our laboratory demonstrated that Fpr1−/−mice are protected from CS-induced emphysematous changes, suggesting that formylated peptides within CS are central to disease pathogenesis. A similar beneficial reduction in inflammatory response, with fewer migrating neutrophils and macrophages and lower proinflammatory cytokine levels, was observed after acute or subacute exposure to CS. Further support for the role of FPRs in COPD pathogenesis has come from additional experimental studies in which alterations resembling COPD are induced in mice by a single intratracheal instillation of formylated peptides.32, 49 Actually, these receptors are overexpressed in patients with COPD, and, in established COPD, FPR activation by formyl-peptides released from mitochondria of necrotic Cathepsin S inhibitor or bacteria (that usually colonize pulmonary structures) may promote persistent inflammation by feeding the vicious cycle that causes persistent inflammation after SC.
    Introduction Formyl-peptide receptors (FPRs) are a family of seven transmembrane domains, Gi-protein-coupled receptors (GPCRs). In human, there are 3 FPRs, FPR1, FPR2 and FPR3. FPR1 and FPR2 were originally identified based on their capacity to recognize N-formyl peptides produced in nature by degradation of either bacterial [1], [2], [3], [4] or host cell mitochondrial proteins, which represent major proinflammatory products [5], [6]. Activation of FPR1 and FPR2 by chemotactic agonists elicits a cascade of signaling events leading to myeloid cell migration, mediator release, increased phagocytosis and new gene transcription [7]. But for FPR3, although it is expressed in monocytes and dendritic cells (DCs), the overall function remains unclear. Compared to FPR1 and FPR2, FPR3 is highly phosphorylated (a signal for receptor inactivation and internalization) and more localized to small intracellular vesicles [8]. This suggests that FPR3 rapidly internalizes after binding its ligands and thereby may serve as a “decoy” receptor to reduce the binding of its ligands to other receptors [8], [9]. Interestingly, FPR3 does not interact with formylated chemoattract peptides, nor shares ligands with FPR1 or FPR2. Therefore, FPR3 may have its own unique functional significance. The mouse FPR (mFPR or Fpr) gene family consists of at least 8 members including Fpr1, Fpr2, Fpr-rs1, Fpr-rs3, Fpr-rs4, Fpr-rs5, Fpr-rs6, and Fpr-rs7 [4]. Fpr1 is considered as an ortholog of human FPR1, whereas Fpr2 is structurally and functionally like human FPR2 [10]. The mouse counterpart of human FPR3 is not well defined. Since Fpr2 shares a human FPR3 ligand [11], [12], Fpr2 was suggested to act as a counterpart of both FPR2 and FPR3. The other 6 murine Fpr genes are expressed in leukocytes, but the identity of their encoded receptors remain unknown [3]. FPRs are mainly expressed in leukocytes (Table 1) including neutrophils [13], monocytes/macrophages [4], [14], natural killer (NK) cells [15], [16], and DCs [17], [18]. Recently, FPR2 was detected in naive CD4+ T cells (CD3+CD4+CD45RA+CD45RO−CCR7+), human tonsillar follicular helper T cells, Th1 cells, Th2 cells, and Th17 cells [16], [19]. FPR2 is also expressed in follicular DCs and B cells. In B cells located in the germinal center (GC) of Peyer's patches, FPR2 is activated by an endogenous agonist LL-37 [20]. Importantly, FPRs are also expressed in a variety of non-immune cells (Table 2) including endothelial cells, endothelial progenitor cells [21], [22], synovial fibroblasts [23], [24], keratinocytes [25], intestinal epithelial cells [26], bone marrow-derived mesenchymal stem cells (MSCs) [27], [28], and hepatocytes [29], suggesting a broader spectrum of biological function of these receptors (see Table 3)