Key Points• TPO-RAs shift monocyte FcgR balance toward the inhibitory FcgRIIb and correct the enhanced phagocytic capacity of macrophages in ITP.Elevated expression of the activating Fcg receptor (FcgR) I and FcgRIIa together with decreased expression of the inhibitory FcgRIIb are involved in the pathogenesis of primary immune thrombocytopenia (ITP). Thrombopoietin receptor agonists (TPO-RAs) have been used clinically for the management of ITP; however, little is known about the effect of TPO-RAs on FcgR modulation in ITP. In this prospective study, we measured the alteration in monocyte FcgR expression from 21 corticosteroid-resistant/relapsed patients with chronic ITP receiving eltrombopag therapy. Results showed that the mRNA and protein levels of FcgRIIb were significantly elevated after 6-week eltrombopag treatment. Concurrently, FcgRI and IIa levels decreased remarkably, whereas FcgRIII expression did not change. In vitro phagocytosis assays indicated that a shift in the balance of FcgR toward inhibitory FcgRIIb on monocytes was accompanied with a considerable decrease in monocyte/macrophage phagocytic capacity. The response to eltrombopag therapy in patients with ITP was associated with FcgR phenotype and functional changes of monocytes/macrophages. Moreover, the plasma transforming growth factor-b1 (TGF-b1) concentrations increased significantly in eltrombopag responders. Modulation of monocyte FcgR balance by TPO-RAs was also found in a murine model of ITP established by transferring splenocytes from immunized CD61 knockout mice into CD61 1 severe combined immunodeficient mice. Romiplostim administration in ITP mice significantly upregulated inhibitory FcgRII expression and downregulated activating FcgRI expression. These findings showed that recovery of platelet counts after TPO-RA treatment in ITP is associated with the restoration of FcgR balance toward the inhibitory FcgRIIb on monocytes, and suggested that thrombopoietic agents have a profound effect on immune modulation in ITP. This study is registered at ClinicalTrials.gov as #NCT01864512. (Blood. 2016;128(6):852-861)
Key Points• The impaired suppressive function of myeloid-derived suppressor cells plays a role in the pathogenesis of immune thrombocytopenia.• The effect of dexamethasone in correcting dysfunction of myeloid-derived suppressor cells suggests a new therapeutic mechanism of high-dose dexamethasone in patients with immune thrombocytopenia.Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. In this study, the MDSC population was evaluated in adult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCs were impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor b was significantly upregulated in DXM-modulated MDSCs compared with the unmodulated cultures. DXMmodulated MDSCs inhibited autologous CD4 1 T-cell proliferation and significantly attenuated cytotoxic T lymphocyte-mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61 1 platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce a murine model of severe ITP. We passively transferred the DXM-modulated MDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo compared with those receiving splenocyte engraftment alone. These findings suggested that impaired MDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1.
A high fosfomycin resistance rate was observed in Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) in our previous study, but little is known about its mechanisms. In this study, we explored the prevalence of plasmidmediated fosfomycin resistance determinants among fosfomycin-resistant KPC-KP strains from a Chinese university hospital and determined the complete sequence of a novel fosA3-carrying plasmid isolated from an epidemic K. pneumoniae sequence type (ST) 11 strain. A total of 97 KPC-KP strains were studied, of which 57 (58.8%) were resistant to fosfomycin, including 44 (45.4%) harboring fosA3 and 1 harboring fosA. All fosA3-positive strains belonged to the dominant ST11-pulse type (PT) A clone according to multilocus sequence typing and pulsed-field gel electrophoresis, suggesting clonal dissemination. The fosA-positive isolate belonged to ST11-PTE. The fosA3-carrying plasmid pKP1034 is 136,848 bp in length and is not self-transmissible. It is a multireplicon plasmid belonging to IncR-F33:A؊: B؊. Besides fosA3, a variety of other resistance determinants, including bla KPC-2 , rmtB, bla CTX-M-65 , and bla SHV-12 , are identified in pKP1034, which would allow for coselection of fosA3 by most -lactams and/or aminoglycosides and facilitate its dissemination despite limited use of fosfomycin in China. Detailed comparisons with related plasmids revealed that pKP1034 is highly mosaic and might have evolved from alarming recombination of the bla KPC-2 -carrying plasmid pKPC-LK30 from Taiwan and the epidemic fosA3-carrying plasmid pHN7A8 from mainland China. Increasing prevalence of Klebsiella pneumoniae carbapenemaseproducing K. pneumoniae (KPC-KP) has presented an alarming clinical threat. Fosfomycin seems to retain in vitro activity against many carbapenem-resistant Enterobacteriaceae and has been recently reintroduced into the fight against these superbugs, including KPC-KP strains (1-4). A previous study showed that only 43.4% of KPC-KP strains retained susceptibility to fosfomycin in a Chinese university hospital (5). Recently, Jiang et al. reported a comparable fosfomycin susceptibility rate (39.2%) in KPC-KP collected from 12 hospitals in China, and fosfomycin resistance could be attributed to the plasmid-mediated fosA3 gene in 94 (55.6% of fosfomycin-resistant KPC-KP) strains (6).FosA3 inactivates fosfomycin by glutathione S-transferase activity and was characterized first in CTX-M-producing Escherichia coli in Japan (7). Thereafter, it has been detected in foodproducing animals, pets, patients, and healthy individuals in Asian countries (8-11). In most cases, the fosA3 gene is associated with bla CTX-M genes and sometimes with rmtB as well, and it resides on IS26-composite transposons, facilitating its dissemination. More recently, fosA3 has been characterized in two atypical bla KPC -carrying plasmids (6, 12). Here we explored the prevalence of plasmid-mediated fosfomycin resistance determinants among KPC-KP strains from a Chinese university hospital and determined the comple...
Cancer immunotherapy by immune checkpoint blockade has been effective in the treatment of certain tumors. However, the association between immune checkpoints and autoimmune diseases remains elusive and requires urgent investigation. Primary immune thrombocytopenia (ITP), characterized by reduced platelet count and a consequent increased risk of bleeding, is an autoimmune disorder with a hyper-activated T cell response. Here, we investigated the contribution of immune checkpoint-related single-nucleotide polymorphisms (SNPs), including CD28, ICOS, PD1, TNFSF4, DNAM1, TIM3, CTLA4, and LAG3 to the susceptibility and therapeutic effects of ITP. In this case-control study, 307 ITP patients and 295 age-matched healthy participants were recruited. We used the MassARRAY system for genotyping immune checkpoint-related SNPs. Our results revealed that rs1980422 in CD28 was associated with an increased risk of ITP after false discovery rate correction (codominant, CT vs. TT, OR = 1.788, 95% CI = 1.178–2.713, p = 0.006). In addition, CD28 expression at both the mRNA and protein levels was significantly higher in patients with CT than in those with the TT genotype (p = 0.028 and p = 0.001, respectively). Furthermore, the T allele of PD1 rs36084323 was a risk factor for ITP severity and the T allele of DNAM1 rs763361 for corticosteroid-resistance. In contrast, the T allele of LAG3 rs870849 was a protective factor for ITP severity, and the T allele of ICOS rs6726035 was protective against corticosteroid-resistance. The TT/CT genotypes of PD1 rs36084323 also showed an 8.889-fold increase in the risk of developing refractory ITP. This study indicates that immune checkpoint-related SNPs, especially CD28 rs1980422, may be genetic factors associated with the development and treatment of ITP patients. Our results shed new light on prognosis prediction, disease severity, and discovering new therapeutic targets.
Altered microenvironmental stiffness is a hallmark of inflammation. It is sensed by the mechanically activated cation channel Piezo1 in macrophages to induce subsequent immune responses. However, the mechanism by which the mechanosensitive signals shape the metabolic status of macrophages and tune immune responses remains unclear. We revealed that Piezo1-deficient macrophages exhibit reduced aerobic glycolysis in resting or liposaccharide (LPS)-stimulated macrophages with impaired LPS-induced secretion of inflammatory cytokines in vitro. Additionally, pretreatment with the Piezo1 agonist, Yoda1, or cyclical hydrostatic pressure (CHP) upregulated glycolytic activity and enhanced LPS-induced secretion of inflammatory cytokines. Piezo1-deficient mice were less susceptible to dextran sulfate sodium (DSS)-induced colitis, whereas Yoda1 treatment aggravated colitis. Mechanistically, we found that Piezo1 activation promotes aerobic glycolysis through the Ca2+-induced CaMKII-HIF1α axis. Therefore, our study revealed that Piezo1-mediated mechanosensitive signals Piezo1 can enhance aerobic glycolysis and promote the LPS-induced immune response in macrophages.
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