Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Ligand selectivity may directly be

    2021-11-24

    Ligand selectivity may directly be related to the conformational landscape explored by GPCRs despite that most GPCRs do not require dimerization for ligand recognition (Mary et al., 2012). Monomer FPRs have traditionally been perceived as receptors that can recognize N-formyl peptides and LXA4. This view is supported by studies with AnxA1-derived peptide Ac2–26 that was reported to signal through both FPR1 and FPR2/ALX monomers (Cooray et al., 2013). Emerging evidence suggests that FPR2/ALX homodimers and FPR2/ALX-FPR1 heterodimers constitutively occur in human leukocytes and in response to specific ligands and this dimerization alters the activation of downstream signaling pathways (Cooray et al., 2013). AnxA1 and LXA4 stimulate FPR2/ALX homodimerization and activation of the p38MAPK pathway, whereas peptide Ac2–26 facilitates FPR2/ALX-FPR1 heterodimer formation and activation of the JNK-caspase-3 pathway (Cooray et al., 2013, Filep, 2013). AnxA1-stimulated FPR2/ALX homodimerization triggers the production of the anti-inflammatory cytokine IL-10, whereas FPR2/ALX-FPR1 heterodimers propagate pro-apoptotic signaling pathways compared with the pro-survival action of SAA, which does not enhance dimerization (Fig. 1). The functional FPR2/ALX isomer for other ligands, the minimal functional unit for dimers and the interplay between protomers in FPR2/ALX dimers on each other to generate ligand-biased intracellular signals remains, however, to be investigated. It is intriguing that FPR2/ALX agonists with essential roles in host defense also control active inflammation resolution programs. Indeed, LXA4, aspirin-triggered 15-epi-LXA4, RvD1, AnxA1 and peptide Ac2–26 acting predominantly via FPR2/ALX were reported to limit PMN accumulation, promote PMN apoptosis, and stimulate efferocytosis and tissue repair in experimental models of inflammation (Serhan, 2014, Ortega-Gomez et al., 2013). There is evidence indicating that a hierarchy exists among FPR2/ALX ligands (El Kebir et al., 2007, Bozinovski et al., 2012). Since in the inflamed tissues death associated protein kinase receive multiple cues, their fate would ultimately depend on the relative abundance of these mediators. Conceivably, generation of N-formyl peptides and other pro-inflammatory agonists would overcome the functions of endogenous anti-inflammatory FPR2/ALX agonists at the initial phase of acute inflammation, whereas enhanced production of pro-resolving mediators would become more prominent at a later stage, ultimately leading to resolution.
    FPRs as therapeutic targets in human disease While the studies addressing the function of FPRs have largely been conducted with experimental systems, a growing number of clinical studies reported close association of altered patterns of expression of FPRs or some of their ligands with human diseases (Table 3). These observations are important because of potential causal or diagnostic relevance, and paving the way for development of novel therapeutics. In context with diagnostic biomarkers, elevated serum SAA levels have been recognized as prognostic marker for acute coronary artery disease (Jousilahti et al., 2001), acute exacerbations of COPD (Bozinovski et al., 2008) and rheumatoid arthritis (Nakamura, 2008). Another example is presence of elevated FPR1 mRNA levels in the peripheral blood, which might be used as a biomarker for small cell and non-small cell lung cancers (Morris et al., 2018). While the therapeutic potential of FPRs has been recognized for some time, the large variety of FPR ligands, affecting an ever-increasing range of biological functions, make therapeutic approaches challenging to design as indicated by the results from preclinical studies. Arguably development of compounds that can counter the actions of pro-inflammatory ligands without impairing host defense or resolution programs, or even stimulating resolution mechanisms may be the most rewarding avenue to pursue.
    Concluding remarks
    Introduction Migration of leukocytes across the wall of blood vessels into tissues is one of the key events during inflammation, immune response against infection and tissue remodelling, representing a crucial process in the pathogenesis of chronic inflammatory diseases. The urokinase-type plasminogen activator receptor (uPAR) is expressed by a wide variety of hematologic cells, including monocytes, macrophages, and lymphocytes. Interestingly, uPAR plays an important role in inflammation sustained by leukocyte recruitment [1], [2], [3]. Migration of immune cells to tissue lesions is specifically sparked off by the uPAR engagement with its ligand urokinase (uPA) as previously verified in uPA−/− and uPAR−/− mice, which showed impairment of host defences, bacterial spread, and finally death [3], [4], [5], [6], [7]. Moreover, plasma levels of soluble forms of uPAR have been detected in plasma of individuals affected by viral, bacterial or parasitic infections as well as autoimmune diseases [8], [9].