Correlation between thrombopoietin and inflammatory factors, platelet indices, and thrombosis in patients with sepsis: A retrospective study.

BACKGROUND: Thrombopoietin (TPO) is a primary regulator of thrombopoiesis in physiological conditions. TPO, in combination with its specific cytokine receptor c-Mpl, drives platelet production by inducing the proliferation and differentiation of megakaryocytes. However, the role of TPO in sepsis is not well determined. The elevated levels of TPO are often accompanied by a decrease of platelet count (PLT) in systemic infected conditions, which is contrary to the view that TPO promotes platelet production under physiological conditions. In addition, whether TPO mediates organ damage in sepsis remains controversial. AIM: To explore the relationships between TPO and inflammatory factors, platelet indices, and thrombotic indicators in sepsis. METHODS: A total of 90 patients with sepsis diagnosed and treated at the emergency medicine department of The First People's Hospital of Foshan between January 2020 and March 2021 were enrolled in this study. In addition, 110 patients without sepsis who came to the emergency medicine department were included as controls. Clinical and laboratory parameters including age, gender, TPO, blood cell count in peripheral blood, platelet indices, inflammatory factors such as high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-21, and IL-6, organ damage indicators, and thrombotic indicators were collected and analyzed by using various statistical approaches. RESULTS: The results showed that the TPO levels were higher in the sepsis group than in controls [86.45 (30.55, 193.1) vs 12.45 (0.64, 46.09) pg/mL, P < 0.001], but PLT was lower (P < 0.001). Multivariable analysis showed that white blood cell count (WBC) [odds ratio (OR) = 1.32; 95% confidence interval (CI): 1.01-1.722; P = 0.044], TPO (OR = 1.02; 95%CI: 1.01-1.04; P = 0.009), IL-21 (OR = 1.02; 95%CI: 1.00-1.03; P = 0.019), troponin I (OR = 55.20; 95%CI: 5.69-535.90; P = 0.001), and prothrombin time (PT) (OR = 2.24; 95%CI: 1.10-4.55; P = 0.027) were independent risk factors associated with sepsis. TPO levels were positively correlated with IL-21, IL-6, hs-CRP, creatinine, D-dimer, PT, activated prothrombin time, international normalized ratio, fibrinogen, WBC count, and neutrophil count, and negatively correlated with PLT, thrombin time, red blood cell count, and hemoglobin concentration (P < 0.05). Receiver operating characteristic analysis showed that TPO had fair predictive value in distinguishing septic patients and non-septic patients (the area under the curve: 0.788; 95%CI: 0.723-0.852; P < 0.001). With an optimized cutoff value (28.51 pg/mL), TPO had the highest sensitivity (79%) and specificity (65%). CONCLUSION: TPO levels are independently associated with sepsis. High TPO levels and low PLT suggest that TPO might be an acute-phase response protein in patients with infection.

Cyclooxygenase-1 Regulates the Development of Follicular Th Cells via Prostaglandin E2.

Cyclooxygenase (COX)-1, one of the critical enzymes required for the conversion of arachidonic acid to PGs, has been demonstrated to play an important role not only in the cardiovascular system but also in the immune system. COX-1 has been found to regulate early B cell differentiation, germinal center formation, and Ab production of B cells. However, the underlying mechanisms of COX-1-mediated B cell activation remains not fully understood. In this study, we reported that COX-1 is a potential regulator for the development of follicular Th (TFH) cells. COX-1-deficient (COX-1-/- ) mice displayed a significant reduction of TFH cells upon influenza infection or immunization with keyhole limpet hemocyanin, which led to a severe impairment of germinal center responses. We further demonstrated that COX-1-derived PGE2, via binding with its receptors EP2/EP4, represents the underlying mechanism. The administration of EP2/EP4 agonists or PGE2 almost completely rescued the defective TFH cell generation in COX-1-/- mice. Taken together, our observations indicate that COX-1 plays an important role in the development of TFH cells.

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells.

Glucocorticoids (GCs) used as inflammation suppressors have harmful side effects, including induction of hepatic steatosis. The underlying mechanisms of GC-promoted dysregulation of lipid metabolism, however, are not fully understood. GCs could facilitate the accumulation of myeloid-derived suppressor cells (MDSC) in the liver of animals, and the potential role of MDSCs in GC-induced hepatic steatosis was therefore investigated in this study. We demonstrated that granulocytic (G)-MDSC accumulation mediated the effects of GCs on the fatty liver, in which activating transcription factor 3 (ATF3)/S100A9 signaling plays an important role. ATF3-deficient mice developed hepatic steatosis and displayed expansion of G-MDSCs in the liver and multiple immune organs, which shared high similarity with the phenotype observed in GC-treated wild-type littermates. Adoptive transfer of GC-induced or ATF3-deficient G-MDSCs promoted lipid accumulation in the liver, whereas depletion of G-MDSCs alleviated these effects. Mechanistic studies showed that in MDSCs, ATF3 was transrepressed by the GC receptor GR through direct binding to the negative GR-response element. S100A9 is the major transcriptional target of ATF3 in G-MDSCs. Silencing S100A9 clearly alleviated G-MDSCs expansion and hepatic steatosis caused by ATF3 deficiency or GC treatment. Our study uncovers an important role of G-MDSCs in GC-induced hepatic steatosis, in which ATF3 may have potential therapeutic implications.

Myeloid-derived suppressor cells are essential for maintaining feto-maternal immunotolerance via STAT3 signaling in mice.

Maternal immune system tolerance to the semiallogeneic fetus is essential for a successful pregnancy; however, the mechanisms underlying this immunotolerance have not been fully elucidated. Here, we demonstrate that myeloid-derived suppressor cells play an important role in maintaining feto-maternal tolerance. A significant expansion of granulocytic myeloid-derived suppressor cells was observed in multiple immune organs and decidual tissues from pregnant mice. Pregnancy-derived granulocytic myeloid-derived suppressor cells suppressed T cell responses in a reactive oxygen species-dependent manner and required direct cell-cell contact. Mechanistic studies showed that progesterone facilitated differentiation and activation of granulocytic myeloid-derived suppressor cells, mediated through STAT3 signaling. The STAT3 inhibitor JSI-124 and a specific short hairpin RNA completely abrogated the effects of progesterone on granulocytic myeloid-derived suppressor cells. More importantly, granulocytic myeloid-derived suppressor cell depletion dramatically enhanced the abortion rate in normal pregnant mice, whereas adoptive transfer of granulocytic myeloid-derived suppressor cells clearly reduced the abortion rate in the CBA/J X DBA/2J mouse model of spontaneous abortion. These observations collectively demonstrate that granulocytic myeloid-derived suppressor cells play an essential role in the maintenance of fetal immunotolerance in mice. Furthermore, our study supports the notion that in addition to their well-recognized roles under pathologic conditions, myeloid-derived suppressor cells perform important functions under certain physiologic circumstances.