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  • br Role of FPRs in regulating the inflammatory

    2022-05-26


    Role of FPRs in regulating the inflammatory response Annexin I is a glucocorticoid-regulated protein possessing both pro- and anti-inflammatory activity that might be mediated, in part, by FPR activation [35]. Expressed in a variety of cell types, annexin I is particularly abundant in neutrophils. It is externalized onto the neutrophil cell surface and acts to inhibit transendothelial migration [36]. Although both annexin I holoprotein and its N-terminal peptides (Ac1–26 and Ac9–25) are FPR agonists [35], at low concentrations they elicit Ca2+ transients through FPRs without fully activating the MAP kinase pathway. This is associated with neutrophil desensitization and inhibition of transendothelial migration induced by other chemoattractants, such as the chemokine interleukin (IL)-8. By contrast, at high concentrations, annexin I peptides fully activate neutrophils in vitro and become potent proinflammatory stimulants. The anti-migratory activity of exogenous and endogenous annexin I has been shown in both acute and chronic models of inflammation 37., 38.. FPR−/− mice [39] exhibit normal neutrophil accumulation during thioglycollate-elicited peritonitis, however, a significant reduction of peritoneal neutrophil infiltration observed in annexin I-treated wild-type mice was abolished in FPR−/− mice. Recent research shows that a human lung epithelial carcinoma cell line, A549, expresses FPR and responds to both fMLF and annexin I by the secretion of acute-phase proteins [40]. Thus, activation of nonmyeloid FPR by the host-derived ligand annexin I could participate in the regulation of acute-phase responses during inflammation. However, this hypothesis requires confirmation by studies of normal alveolar epithelia. The lipid mediator LXA4 and its aspirin-triggered isomer 15-epi-LXA4, are both potent agonists of FPRL1 [41]. To our knowledge FPRL1 is the only known chemotactic GPCR that has both endogenous peptide and lipid ligands. LXA4 and 15-epi-LXA4 are generated during multicellular interactions in inflammation and tissue injury (reviewed in [42]). Both mediators induce chemotaxis of FPRL1-transfected Chinese hamster ovary (CHO) KX2-391 [43] and Ca2+ flux in human monocytes in vitro[44]. However, the most prominent biological activity reported for LXA4 is the inhibition of neutrophil-mediated proinflammatory responses. LXA4 suppresses the activation of FPRL1 by its peptide agonists [43] and in addition, inhibits the activation of neutrophils or epithelial cells by proinflammatory cytokines acting through receptors distinct from FPRL1 [45]. How LXA4 is capable of eliciting pro- versus anti-inflammatory signals through FPRL1 in different cell types is puzzling. Recent research shows that LXA4 and its stable analogues induce small G-protein dependent actin reorganization in monocytes but not in neutrophils [46]. This provides evidence for the distinction between two cell types in their signaling pathways elicited by LXA4 and supports the hypothesis that LXA4 could contribute to the conversion of inflammatory responses from the acute to the chronic phase by inhibiting neutrophil, but promoting monocyte, recruitment. However, confirmation is required concerning the dual roles of LXA4 in inflammation, acting solely on FPRL1 (and its murine analogue) or on multiple receptors, such as an leukotriene D4 (LTD4) receptor [47]. The new knowledge about FPRL1 ligands has led to the discovery of LXA4 activity in regulating Th1 immune responses in a murine model of Toxoplasma gondii infection, which is characterized by a rapid, but transient, CCR5-mediated production of IL-12 p40 by splenic CD8α+ DCs in response to tail vein injection of STAg, a soluble extract of Toxoplasma tachyzoites. Aliberti et al.[48] found that LXA4, produced by macrophages in infected animals, has a crucial role in downregulating CCR5 and IL-12 production by splenic DCs, a phenomenon known as DC paralysis. The model suggests that LXA4 could serve as an anti-inflammatory regulator, maintaining a balance between the beneficial effects of IL-12 in innate and Th1 immune responses and its potential for toxicity at high concentrations. Despite the potential role that FPRL1 had with regard to hypothesis generation in this research, the precise role of its murine counterpart (known as LXA4R, the product of the gene Fpr-rs1) [25] in STAg-induced DC paralysis is undefined. The expression and function of formyl-peptide receptors in murine DCs also require characterization for comparison with human myeloid DCs 21., 22..