Sepsis remains a leading cause of death worldwide, despite advances in critical care, and understanding of the pathophysiology and treatment strategies. No specific therapy or drugs are available for sepsis. Neutrophils play a critical role in controlling infection under normal conditions, and it is suggested that their migration and antimicrobial activity are impaired during sepsis which contribute to the dysregulation of immune responses. Recent studies further demonstrated that interruption or reversal of the impaired migration and antimicrobial function of neutrophils improves the outcome of sepsis in animal models. In this review, we provide an overview of the associated mediators and signal pathways involved which govern the survival, migration and antimicrobial function of neutrophils in sepsis, and discuss the potential of neutrophils as a target to specifically diagnose and/or predict the outcome of sepsis.

Endocytic recycling of internalized transmembrane proteins is essential for many important physiological processes. Recent studies have revealed that retromer-related Sorting Nexin family (SNX)-Bin/Amphiphysin/Rvs (BAR) proteins can directly recognize cargoes like cation-independent mannose 6-phosphate receptor (CI-MPR) and Insulin-like growth factor 1 receptor (IGF1R); however, it remains poorly understood how SNX-BARs select specific cargo proteins and whether they recognize additional ligands. Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. Using this motif, we identified over 70 putative SNX-BAR ligands, many of which play critical roles in apoptosis, cell adhesion, signal transduction, or metabolite homeostasis. Remarkably, SNX-BARs could cooperate with both SNX27 and retromer in the recycling of ligands encompassing the SBM, PDZ-binding motif, or both motifs. Overall, our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.have been linked with a variety of human diseases including Alzheimer's disease, Parkinson's disease, cancer, and diabetes [4,5].Key protein machineries important for the sequence-dependent recycling include the evolutionarily conserved retromer complex (vacuolar protein sorting 35 [VPS35]/VPS26/VPS29 in higher eukaryotes) [6][7][8], the recently discovered retriever [9], the WASH complex [10][11][12], and members of the Sorting Nexin family (SNX) [13][14][15]. A subset of SNX proteins possessing a Bin/Amphiphysin/Rvs (BAR) domain, in addition to the phox-homology (PX) domain, have been linked with the retromer complex. The retromer-related SNX-BAR proteins (referred as SNX-BARs herein) SNX1, SNX2, SNX5, SNX6, and SNX32 form heterodimeric complexes and are critical for both endosome-to-plasma membrane recycling and endosome-to-TGN retrieval [16,17]. Current models suggest that SNX-BARs promote the endosome-to-plasma membrane recycling via associating with SNX27 and retromer, with the PDZ domain of SNX27 as the predominant cargo-recognition module [14]. For endosome-to-TGN trafficking, one of the best-characterized cargoes is cation-independent mannose 6-phosphate receptor (CI-MPR), which is necessary to deliver newly synthesized lysosomal hydrolases to the endosomal lumen and thus critical for lysosomal function [18]. However, previous studies have provided contradictory models regarding the role of retromer and SNX-BARs in the endosome-to-TGN retrieval of CI-MPR. Work from many different labs has initially supported the idea that retromer is necessary for the retrieval of CI-MPR, likely through a direct association with its cytoplasmic tail, in particular, the hydrophobic WLM motif [19][20][21]. However, recent work by Cullen and Steinberg has provi...

Wild-type p53-induced phosphatase 1 (Wip1) is a newly identified serine/threonine phosphatase, which belongs to the PP2C family. Due to its involvement in stress-induced networks and overexpression in human tumors, primary studies have mainly focused on the role of Wip1 in tumorigenesis. It now has also been implicated in regulating several other physiological processes such as organism aging and neurogenesis. Recent evidence highlights a new role of Wip1 in controlling immune response through regulating immune cell development and function, as well as through the interplay with inflammatory signaling pathways such NF-κB and p38 mitogen-activated protein kinase. In this short review, we will give an overview of Wip1 in immunity to better understand this important phosphatase.

Studies clearly showed that CD52 can modulate T-cell activation either by its intracellular signal pathways or by the interaction of soluble CD52 and Siglec-10 expressing on T cells. However, the regulatory functions of CD52 on other immune cell subpopulations in organ transplantation require to be studied in the near future.

Pontocerebellar hypoplasia (PCH) is a group of neurological disorders that affect the development of the brain, in particular, the pons and cerebellum. Homozygous mutations of TBC1D23 have been found recently to lead to PCH; however, the underlying molecular mechanisms remain unclear. Here, we show that the crystal structure of the TBC1D23 C-terminal domain adopts a Pleckstrin homology domain fold and selectively binds to phosphoinositides, in particular, PtdIns(4)P, through one surface while binding FAM21 via the opposite surface. Mutation of key residues of TBC1D23 or FAM21 selectively disrupts the endosomal vesicular trafficking toward the Trans-Golgi Network. Finally, using the zebrafish model, we show that PCH patient-derived mutants, impacting either phosphoinositide binding or FAM21 binding, lead to abnormal neuronal growth and brain development. Taken together, our data provide a molecular basis for the interaction between TBC1D23 and FAM21, and suggest a plausible role for PtdIns(4)P in the TBC1D23-mediating endosome-to-TGN trafficking pathway. Defects in this trafficking pathway are, at least partially, responsible for the pathogenesis of certain types of PCH.

Dietary consumption of functional foods enriched in anthocyanins benefit for human health by protection against far-ranging human diseases. Delphinidin-derived anthocyanins (valuable as blue pigments and antioxidants) are accumulated specifically in the fruits of Lycium ruthenicum but not in the fruits of Lycium barbarum, suggesting the differences of anthocyanin biosynthesis between the two species. In this study, anthocyanin profiling confirmed that anthocyanins were increasingly accumulated during fruit ripening in L. ruthenicum, and sharply increased at full expanded mature fruit, while no anthocyanin were detected at any stage of L. barbarum fruit development. Several genes involved in anthocyanin biosynthesis were characterized in L. ruthenicum and L. barbarum fruits. Expression profiling of these genes during fruit development showed a significant positive correlation between transcript abundance and anthocyanin accumulation in L. ruthenicum fruit. Meanwhile, transcripts in L. barbarum fruit were either undetectable or were downregulated during fruit ripening, before increasing slightly in the final stages of maturation. In addition, the ratio of LrF3'5H/LrF3'H transcription showed a gradual increase before 6 days after breaker (DAB) and a sharp enhancement at 10 DAB. Our results suggest that the expression patterns of both regulatory and structural genes and the transcriptional ratio of branch-node structural genes F3'5'H/F3'H may determine the phenotypic difference in anthocyanin biosynthesis between L. ruthenicum and L. barbarum fruits.

Monocytes and macrophages play a key role in defending pathogens, removing the dead cells or cell debris, and wound healing. The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RPM) is widely used in clinics to treat patients with organ transplantation or tumors. The role of mTOR in monocyte/macrophage development remains to be clarified. Here we found that mTOR intrinsically controls monocyte/macrophage development, as evidenced by the decreased percentages and cell numbers of CD11bF4/80 cells resulting from mTOR inhibition in SCID mice, mTOR-deficient mice, and mixed chimera mice, and the in vitro colony formation and monocyte/macrophage induction assays. However, Lyzs-mTOR knockout mice displayed normal levels of monocytes/macrophages, indicating that mTOR is not essential for the survival and maturation of monocytes/macrophages. Further studies showed that mTOR deficiency significantly reduced macrophage colony-stimulating factor receptor CD115 expression at the transcriptional and translational levels. The molecular mechanism studies indicate that the impaired monocyte/macrophage development caused by mTOR deficiency is mainly a result of the overactivated STAT5 and subsequent downregulation of IRF8, but not the altered cell metabolism and autophagy. Therefore, our work identifies that mTOR is an intrinsic master for monocyte/macrophage development at the early stages through regulating STAT5-IRF8-dependent CD115-expressing pathway. Long-term usage of RPM may cause a defect of myeloid progenitors in bone marrow.

How to induce immune tolerance without long-term need for immunosuppressive drugs has always been a central problem in solid organ transplantation. Modulating immunoregulatory cells represents a potential target to resolve this problem. Myeloid-derived suppressor cells (MDSCs) are novel key immunoregulatory cells in the context of tumor development or transplantation, and can be generated in vitro. However, none of current systems for in vitro differentiation of MDSCs have successfully achieved long-term immune tolerance. Herein, we combined dexamethasone (Dex), which is a classic immune regulatory drug in the clinic, with common MDSCs inducing cytokine granulocyte macrophage colony stimulating factor (GM-CSF) to generate MDSCs in vitro. Addition of Dex into GM-CSF system specifically increased the number of CD11b+ Gr-1int/low MDSCs with an enhanced immunosuppressive function in vitro. Adoptive transfer of these MDSCs significantly prolonged heart allograft survival and also favored the expansion of regulatory T cells in vivo. Mechanistic studies showed that inducible nitric oxide sythase (iNOS) signaling was required for MDSCs in the control of T-cell response and glucocorticoid receptor (GR) signaling played a critical role in the recruitment of transferred MDSCs into allograft through upregulating CXCR2 expression on MDSCs. Blockade of GR signaling with its specific inhibitor or genetic deletion of iNOS reversed the protective effect of Dex-induced MDSCs on allograft rejection. Together, our results indicated that co-application of Dex and GM-CSF may be a new and important strategy for the induction of potent MDSCs to achieve immune tolerance in organ transplantation.