Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 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
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • miR a and miR b are two miRNAs of the

    2018-11-05

    miR-146a and miR-146b are two miRNAs of the same family that share the same seed sequence and only differ by two nucleotides at the 3′ end in their mature sequences. However, they are encoded by distinct genes located on separate chromosomes, which implies that they may fulfil distinct functions. Indeed, experimental evidences have demonstrated that both miR-146a and miR-146b are involved in the regulation of macrophage activation, but their target genes and biological roles are different (Nahid et al., 2011; Saba et al., 2014). The gene encoding miR-146a in macrophages was rapidly induced by pro-inflammatory factors, such as LPS and IL-1β, which activate the nuclear factor kappa B (NF-κB) pathway, but the elevated miR-146a blocks further activation of NF-κB signaling, forming a negative feedback loop (Perry et al., 2008; Taganov et al., 2006). While miR-146b expression is also enforced in the macrophages by LPS stimulation with delayed kinetics with respect to miR-146a and via an IL-10-mediated STAT3-dependent transcription, indicating that miR-146b is involved in the IL-10-dependent resolution phase of inflammation (Curtale et al., 2013). In addition, several studies have revealed that miR-146a directly inhibits the activation of M1 macrophage and plays an important role in the pathogenesis of human diseases, such as Brugia malayi infection (Rückerl et al., 2012), mycobacterial exposure (Li et al., 2016), and nephropathy (Bhatt et al., 2016). By contrast, miR-146b has not been reported to have such a function. In this study, we found that, although both miR-146a and miR-146b were upregulated in the process of schistosome infection, only miR-146b could be induced by a series of Th2 cytokines involved in the chronic stage of infection, by activating STAT3/6, and the Th2 cytokines, at least partly, inhibited the differentiation of macrophages to M1 Deazaneplanocin by induction of miR-146b through targeting STAT1. Thus, our study further demonstrated the distinct regulations and biological roles of miR-146a and miR-146b in macrophages. Importantly, data from this study reveal an inhibitory effect of Th2 cytokines such as IL-10 and IL-4/13 on the activation of M1 macrophages through induction of miR-146b.
    Funding Sources
    Conflict of Interest
    Author Contributions
    Acknowledgments
    Introduction Asymptomatic, low-density infections constitute over 60% of the human reservoir of malaria parasite (Laishram et al., 2012) and this combined with long periods of carriage without progression to clinical disease (Bereczky et al., 2004), even in low transmission settings, suggests that asymptomatically infected individuals may contribute substantially to malaria transmission (Alves et al., 2005; Mwesigwa et al., 2015). In contrast, clinical malaria cases have been associated with higher parasite densities. However, the relation between pre-treatment asexual parasite density and gametocyte prevalence after treatment has not been consistent. Antimalarial treatment clears the asexual parasite load which in turn reduces gametocyte burden but clearance of mature gametocytes present prior to treatment is incomplete and varies by treatment (WWARN Gametocyte Study Group, 2016). Therefore, for interrupting malaria transmission and eventual elimination, efficient surveillance and treatment of all persons infected with both asexual stages and gametocytes (Slater et al., 2015) is important. Primaquine (PQ), an 8-aminoquinoline, is recommended in combination with an artemisinin-based combination therapy (ACT) in low Plasmodium falciparum transmission settings to further reduce transmission (World Health Organization, 2010). These drugs act complimentarily: ACTs rapidly clear the P. falciparum asexual parasite biomass as well as early gametocyte stages (Chotivanich et al., 2006), considerably reducing post-treatment gametocyte carriage (WWARN Gametocyte Study Group, 2016) while PQ clears mature gametocytes (White, 2008). However, implementation has been slow because PQ causes a dose-dependent hemolysis, particularly in individuals with some deficiency of the red blood cell enzyme, glucose 6-phosphate dehydrogenase (G6PD) (Eziefula et al., 2014b). The mean prevalence of G6PD deficiency variant in sub-Saharan Africa is 7.5% (Nkhoma et al., 2009) but varies significantly by and within country (Howes et al., 2012). Lower PQ doses may reduce the risk of hemolytic events. The recommended dose was recently reduced from 0·75mg base/kg to 0·25mg base/kg to minimize this risk of hemolysis (Global Malaria Programme, 2015) while presumably retaining efficacy (Ashley et al., 2014; White et al., 2012). PQ\'s mode of action is unclear but may act by sterilizing gametocytes and thus preventing fertilization in the mosquito; this effect precedes clearance of gametocytes from circulation (White, 2013). The presence of circulating gametocytes is thus a poor predictor of transmissibility (Karunajeewa and Mueller, 2016). The efficacy of PQ has been measured by gametocyte clearance and infectiousness to mosquitoes. However, infectiousness studies are not well standardized and this affects their suitability for evaluating efficacy of transmission-blocking interventions (Bousema et al., 2012).