MIR-155 PROMOTES ACUTE ORGAN INJURY IN LPS-INDUCED ENDOTOXEMIC MICE BY ENHANCING CCL-2 EXPRESSION IN MACROPHAGES.

ABSTRACT: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Macrophages play important roles in the inflammatory process of sepsis by secreting chemokines. Chemokine (CC-motif) ligand 2 (CCL-2) is one of the main proinflammatory chemokines secreted by macrophages that plays a critical role in the recruitment of more monocytes and macrophages to the sites of injury in sepsis, but the mechanisms that regulate CCL-2 expression in macrophages during sepsis are still unknown. In the present study, by using the LPS-induced endotoxemia model, we found that LPS induced the expression of microRNA (miR)-155 and CCL-2 in endotoxemic mice and RAW264.7 cells. MiR-155 mimics or miR-155 inhibitor treatment experiment suggested that miR-155 was sufficient to increase LPS-induced CCL-2 expression in macrophages, but miR-155 was not the only factor promoting CCL-2 expression. We further demonstrated that miR-155-induced increase of CCL-2 promoted chemotaxis of additional macrophages, which subsequently enhanced lung injury in endotoxemic mice. Serum/glucocorticoid regulated kinase family member 3 (SGK3), a potential target of miR-155, was identified by RNA sequencing and predicted by TargetScan and miRDB. We further confirmed miR-155 regulated SGK3 to increase LPS-induced CCL-2 by using miR-155 mimics and SGK3 overexpression. Thus, our study demonstrates that miR-155 targets SGK3 to increase LPS-induced CCL-2 expression in macrophages, which promotes macrophage chemotaxis and enhances organs injury during endotoxemia. Our study contributed to a better understanding of the mechanisms underlying the inflammatory response during sepsis.

Vaccination against the HDL receptor of S. japonicum inhibits egg embryonation and prevents fatal hepatic complication in rabbit model.

BACKGROUND: Schistosomiasis is one of the most important neglected tropical infectious diseases to overcome and the primary cause of its pathogenesis is ectopic maturation of the parasite eggs. Uptake of cholesteryl ester from the host high-density lipoprotein (HDL) is a key in this process in Schistosoma japonicum and CD36-related protein (CD36RP) has been identified as the receptor for this reaction. Antibody against the extracellular domain of CD36RP (Ex160) efficiently blocked the HDL cholesteryl ester uptake and the egg embryonation in vitro. However, whether Ex160 immunization could efficiently raise proper antibody responses to sufficiently block HDL cholesteryl ester uptake and the egg embryonation to protect host in vivo is very interesting but unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, rabbits were immunized with the recombinant Ex160 peptide (rEx160) to evaluate its anti-pathogenic vaccine potential. Immunization with rEx160 induced consistent anti-Ex160 IgG antibody and significant reduction in development of the liver granulomatosis lesions associated with suppressed intrahepatic maturation of the schistosome eggs. The immunization with rEx160 rescued reduction of serum HDL by the infection without changing its size distribution, being consistent with interference of the HDL lipid uptake by the parasites or their eggs by antibody against Ex160 in in vitro culture. CONCLUSIONS/SIGNIFICANCE: The results demonstrated that vaccination strategy against nutritional supply pathway of the parasite is effective for reducing its pathogenesis.

Schistosome egg antigen stimulates the secretion of miR-33-carrying extracellular vesicles from macrophages to promote hepatic stellate cell activation and liver fibrosis in schistosomiasis.

Schistosomiasis is a serious and neglected disease with a high prevalence in tropical and subtropical countries. The primary pathology of hepatic schistosomiasis caused by Schistosoma japonicum (S. japonicum) or Schistosoma mansoni (S. mansoni) infection is egg-induced granuloma and subsequent fibrosis in the liver. Activation of hepatic stellate cells (HSCs) is the central driver of liver fibrosis. Macrophages (Mφ), making up 30% of cells in hepatic granulomas, directly or indirectly regulate HSC activation by paracrine mechanisms, via secreting cytokines or chemokines. Currently, Mφ-derived extracellular vesicles (EVs) are broadly involved in cell communication with adjacent cell populations. However, whether Mφ-derived EVs could target neighboring HSCs to regulate their activation during schistosome infection remains largely unknown. Schistosome egg antigen (SEA) is considered to be the main pathogenic complex mixture involved in liver pathology. Here, we demonstrated that SEA induced Mφ to produce abundant extracellular vesicles, which directly activated HSCs by activating their autocrine TGF-ß1 signaling. Mechanistically, EVs derived from SEA-stimulated Mφ contained increased miR-33, which were transferred into HSCs and subsequently upregulated autocrine TGF-ß1 in HSCs through targeting and downregulating SOCS3 expression, thereby promoting HSC activation. Finally, we validated that EVs derived from SEA-stimulated Mφ utilized enclosed miR-33 to promote HSC activation and liver fibrosis in S. japonicum-infected mice. Overall, our study indicates that Mφ-derived EVs play important roles in the paracrine regulation of HSCs during the progression of hepatic schistosomiasis, representing a potential target for the prevention of liver fibrosis in hepatic schistosomiasis.

Synthesis and Electrochemical Properties of Two-Dimensional Hafnium Carbide.

We demonstrate fabrication of a two-dimensional Hf-containing MXene, Hf3C2Tz, by selective etching of a layered parent Hf3[Al(Si)]4C6 compound. A substitutional solution of Si on Al sites effectively weakened the interfacial adhesion between Hf-C and Al(Si)-C sublayers within the unit cell of the parent compound, facilitating the subsequent selective etching. The underlying mechanism of the Si-alloying-facilitated etching process is thoroughly studied by first-principles density functional calculations. The result showed that more valence electrons of Si than Al weaken the adhesive energy of the etching interface. The MXenes were determined to be flexible and conductive. Moreover, this 2D Hf-containing MXene material showed reversible volumetric capacities of 1567 and 504 mAh cm-3 for lithium and sodium ions batteries, respectively, at a current density of 200 mAg-1 after 200 cycles. Thus, Hf3C2Tz MXenes with a 2D structure are candidate anode materials for metal-ion intercalation, especially for applications where size matters.

Synthesis of Zeolitic Imidazolate Framework-7 in a Water/Ethanol Mixture and Its Ethanol-Induced Reversible Phase Transition.

Room to breathe: An efficient method for the synthesis of zeolitic imidazolate framework-7 (ZIF-7) in ethanol/water at room temperature is reported. The ZIF-7 undergoes a reverse-phase transition from large pore (lp)-phase to narrow pore (np)-phase under heat treatment and from np-phase back to lp-phase in ethanol solution.