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
  • On the other hand histone

    2022-01-20

    On the other hand, histone deacetylase inhibitors can accelerate inflammation resolution by promoting the externalization of AnxA1, a main ALX/FPR2 agonist, with concomitant inhibition of cytokine gene expression in mouse macrophages [30]. Thus, our present results provide an additional mechanism, i.e. the upregulation of ALX/FPR2 expression, to explain the pro-resolution activity of histone protein acetylating agents. The assumption that increasing ALX/FPR2 expression corresponds to an enhancement in cellular responses to its agonists was further confirmed by incubating MDA-MB231 p38 inhibitor with LXA4 in the presence or not of 5-aza-dC and CTPB. We selected cell proliferation as functional readout on the basis of previous evidence of LXA4 activity on these cells [32] and also because LXA4 in the majority of cases does not trigger canonical GPCR signaling [33]. For instance, calcium transients were not altered by LXA4 in MDA-MB231 cells (results not shown). As expected, 5-aza-dC and CTPB enhanced LXA4-induced MDA-MB231 cell proliferation (Fig. 3). Together with data with PAEC (Fig. 4), these results are consistent with the evidence that ALX/FPR2 over-expression in myeloid cells protects mice from zymosan-induced peritonitis [20], whereas its downregulation blunts pro-resolution, LXA4- or RvD1-induced human macrophage-dependent bacterial phagocytosis and efferocytosis [17]. Data with KO mice are also consistent with this scenario [34]. In summary, we identified an epigenetic pattern involving H3 serine post-translational modifications that regulates the expression of the ALX/FPR2 receptor. Our findings unveil novel mechanisms that can be investigated in human diseases with inflammatory background, including cancer, and set basis for novel pharmacology based on the potentiation of endogenous pro-resolution pathways.
    Conflict of interest statement
    Funding This work was supported in part by a grant from the Italian Ministry of Education, University and Research to M.R. (PRIN 2010YK7Z5K_002).
    Transparency document
    Acknowledgements
    Introduction Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCR) that play important roles as sensors of pathogen- and host-derived products and recruit leukocytes to sites of infection where these cells exert microbicidal effector functions and clear cellular debris [1], [2]. In humans, there are three FPR isoforms: FPR1, FPR2, and FPR3 [3]. These receptors are expressed on a variety of cell types, including macrophages, neutrophils, T lymphocytes, epithelial cells, dendritic cells, fibroblasts, and astrocytes (reviewed in [3], [4]). Being expressed in the majority of white blood cells, FPRs play an important role in the regulation of inflammatory reactions and cellular dysfunction and, thereby, represent an attractive family of pharmacological targets for therapeutic development [4], [5], [6]. FPR1 exhibits high affinity for formyl peptides, which are produced by bacteria and can also be released from damaged mitochondria during tissue injury [7], p38 inhibitor [8]. In addition, FPR1 has recently been reported to contribute to disease pathogenesis. For example, interaction of endogenous annexin A1 with FPR1 leads to transactivation of the receptor for epithelial growth factor (EGFR), which promotes invasion and growth of glioma cells [2]. Likewise, Cheng et al. [9] reported that FPR1 expression is associated with tumor progression and survival in gastric cancer. Thus, bioactive ligands acting as FPR1 antagonists might serve as useful therapeutics in host defense in order to reduce detrimental effects associated with inflammation and cancer. The receptor-specific and most potent FPR1 antagonists described so far are the fungal hydrophobic cyclic peptides, cyclosporines A and H [10]. Although cyclosporine H blocked N-formyl-Met-Leu-Phe (fMLF)-induced analgesia [11] and attenuated the acute inflammatory response evoked by cigarette smoke [12], in vivo studies of cyclosporines should be interpreted carefully because their main therapeutic effects appear to involve signaling pathways unrelated to FPR1 [13], [14], [15], [16]. Other known peptide FPR antagonists are Boc-1 (Boc-MLF) and Boc-2 (Boc-FLFLFL), and there are several reports of in vivo application of Boc-2 [17], [18], [19], [20]. Recently, analogs of Boc-2 were reported as FPR1 antagonists [21], [22]. Several non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, piroxicam, sulfinpyrazone, and tenoxicam have been reported as low activity FPR1 antagonists [23], [24], [25]. However, because NSAIDs exhibit a variety of pharmacological properties, these drugs are not suitable for in vivo studies designed to probe the physiological roles of FPR1.