Tong Zhou

Our previous study had demonstrated that Runx1 promoted LPS-induced macrophage inflammatory response, however, the role of Runx1 in M2 macrophage polarization still remains largely unknown. This study was conducted to investigate the role of Runx1 in IL-4/IL-13-induced M2 macrophage polarization and its potential regulatory mechanism. We found that exposure of macrophages to IL-4/IL-13 induced a remarkable increasement in Runx1 expression level. Specifically, we established genetically modified mice lacking Runx1 in myeloid cells, including macrophages. RNA-Seq was performed to identify differentially expressed genes (DEGs) between Runx1 knockout and WT control bone marrow-derived macrophages (BMDMs). We identified 686 DEGs, including many genes which were highly expressed in M2 macrophage. In addition, bioinformatics analysis indicated that these DEGs were significantly enriched in extracellular matrix-related processes. Moreover, RT-qPCR analysis showed that there was an obvious upregulation in the relative expression levels of M2 marker genes, including Arg1, Ym1, Fizz1, CD71, Mmp9, and Tgm2, in Runx1 knockout macrophages, as compared to WT controls. Consistently, similar results were obtained in the protein and enzymatic activity levels of Arg1. Finally, we found that the STAT6 phosphorylation level was significantly enhanced in Runx1 knockout macrophages, and the STAT6 inhibitor AS1517499 partly reduced the upregulated effect of Runx1 deficiency on the M2 macrophage polarization. Taken together, Runx1 deficiency facilitates IL-4/IL-13-induced M2 macrophage polarization through enhancing STAT6 phosphorylation.

The inflammatory response in acute pancreatitis (AP) is associated with acinar-to-dendritic cell transition. The CD4⁺ T-cell-mediated adaptive immune response is necessary for pancreatic inflammatory damage. However, the effect of acinar-to-dendritic cell transition on the CD4⁺ T-cell response and the regulatory mechanism remain undefined. A mouse animal model of AP was established by repeated intraperitoneal injection of CAE. The mTOR inhibitor rapamycin was administered before AP induction. Primary acinar cells were isolated and co-incubated with subsets of differentiated CD4⁺ T cells. The expression of DC-SIGN was also assessed in pancreatic tissues from human AP patients. We found acinar cells expressed DC-SIGN and displayed the phenotype of dendritic cells (DCs), which promoted the differentiation of naive CD4⁺ T cells into CD4⁺/IFN-γ⁺ Th1 and CD4⁺/IL-17A⁺ Th17 cells in pancreatic tissues during AP. DC-SIGN was the target gene of Myc. The mTOR inhibitor rapamycin inhibited AP-induced DC-SIGN expression, CD4⁺ Th1/Th17 cell differentiation and the pro-inflammatory response via Myc. Acinar cells expressed DC-SIGN in pancreatic tissues of human patients with AP. In conclusion, acinar-to-dendritic cell transition is implicated in the CD4⁺ T-cell immune response via mTOR-Myc-DC-SIGN axis, which might be an effective target for the prevention of local pancreatic inflammation in AP.

To investigate the unique features of inflammatory bowel disease (IBD) in children, we wanted to identify whether there might be a strong correlation between the disease phenotype and its prognosis at various ages in paediatric patients. We collected data from patients diagnosed with IBD (ulcerative colitis (UC) or Crohn’s disease (CD)) from 2002 to 2016. The diagnosis was made according to the Porto criteria and Paris Classification. Patient characteristics, clinical manifestations and treatments were collected. Risk factors for surgery, mortality and relapse were analysed by Cox proportional hazard models. Of the 143 patients, 113 had CD, and 30 had UC; there were 89 males and 54 females with a median age of 9 years (y). Thirteen patients in the 0–2 y group were identified as having mutations in IL-10 receptor A, and this mutation was significantly more common in this age group than in 3–9 and 10–16 y patients. The risk factor for surgery was the B3 phenotype; risk factors for death were age 0–2 y and B3 phenotype; 0–2 y, B3 phenotype and steroid dependency were risk factors for early relapse. Clinical manifestations of the onset of IBD in infants and toddlers were extensive and aggressive and were closely associated with early relapse and death. It is of particular interest that some of these patients developed IBD due to monogenic disorders; thus, introduction of genetic testing is essential for these patients.

Considered as true helper cells for B cells in antibody response, Tfh cells are associated with inflammation and immune abnormality. Acute pancreatitis is an acute abdominal disease characterized by inflammatory response and immune disorder. Thus, our objective was to study the frequency of circulating Tfh cells, together with the Tfh cell-related CD4(+) T cells and inflammatory factors in patients with acute pancreatitis. We first examined the frequency of circulating Tfh cell subsets by detecting the expression of CXCR5, PD-1, ICOS and IL-21 by flow cytometry analysis. Then we investigated the abundance of helper T cells and Treg cells. In addition, the plasma level of IgA, IgM, and Tfh cell-related inflammatory factor were detected by cytometric bead array. We showed that the frequency of circulating Tfh cells increased significantly in patients of acute pancreatitis, including CD4(+)CXCR5(+) cells, CD4(+)CXCR5(+)PD-1(+) cells, CD4(+)CXCR5(+)ICOS(+) cells, and CD4(+)CXCR5(+)IL-21(+) cells. Also, increases in plasma IL-1, IL-6, IL-8, IL-17, IL-21 and IgA were observed in patients with acute pancreatitis compared to HCs. This finding indicates that Tfh cells play a vital role in the development and progression of acute pancreatitis that is dependent on IL-6 and IL-21.

Summary: In the pathological process of acute kidney injury (AKI), innate immune receptors are essential in inflammatory response modulation; however, the precise molecular mechanisms are still unclear. Our study sought to demonstrate the inflammatory response mechanisms in renal tubular epithelial cells via Toll-like receptor-4 (TLR-4) and dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin 1 (DC-SIGN) signalling. We found that DC-SIGN exhibited strong expression in renal tubular epithelial cells of human acute renal injury tissues. DC-SIGN protein expression was increased significantly when renal tubular epithelial cells were exposed to lipopolysaccharide (LPS) for a short period. Furthermore, DC-SIGN was involved in the activation of p65 by TLR-4, which excluded p38 and c-Jun N-terminal kinases (JNK). Interleukin (IL)-6 and tumour necrosis factor (TNF)-α expression was decreased after DC-SIGN knock-down, and LPS induced endogenous interactions and plasma membrane co-expression between TLR-4 and DC-SIGN. These results show that DC-SIGN and TLR-4 interactions regulate inflammatory responses in renal tubular epithelial cells and participate in AKI pathogenesis.

The regulation of inflammatory responses by innate immune receptors is recognized as a crucial step in the development of atherosclerosis, although the precise molecular mechanisms remain to be elucidated. This study focused on illustrating the roles of dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)- and Toll-like receptor 4 (TLR4)-regulated inflammatory responses in macrophages. We found that DC-SIGN expression levels were increased in macrophages of atherosclerotic plaques. Oxidized low-density lipoprotein (oxLDL) significantly enhanced DC-SIGN protein expression levels after a short-term exposure. Knockdown of DC-SIGN decreased expression and secretion of interleukin 1-β (IL1-β), monocyte chemo-attractant protein 1 (MCP-1), tumor necrosis factor-α (TNFα) and matrix metalloproteinase-9 (MMP-9). Immunofluorescence studies demonstrated that DC-SIGN and TLR4 co-localized in regions of the plaques. Moreover, DC-SIGN was co-expressed with TLR4 on the plasma membrane after oxLDL stimulation. The presence of an endogenous interaction and the results of the in vitro pull-down assays revealed that DC-SIGN binds directly with TLR4. We also present evidence that DC-SIGN mediates TLR4-regulated NFκB activation but not activation of p38 and JNK. Our results suggest an essential role of DC-SIGN/TLR4 signaling in macrophages in the pathogenesis of atherosclerosis.

H. pylori causes gastritis and increases the risk of gastric ulcer and gastric cancer. However, it was recently shown that H. pylori provides protection against inflammatory bowel diseases. To assess the molecular mechanism of such functions, we studied the role of DCSIGN in H. pylori-infected gastrointestinal epithelial cells. DC-SIGN was found to be over-expressed in the gastric epithelial cells infected with H. pylori and mediated Th1 differentiation, which may be involved in H. pylori-induced gastric mucosal injury. In addition, DC-SIGN was also upregulated in the intestinal epithelial cells derived from colitis mouse model, but the expression levels were blocked upon H. pylori infection, indicating that H. pylori infection may reduce both local and systemic inflammatory responses. In conclusion, we propose that gastrointestinal epithelial cells infected with H. pylori may lead to acquiring of immune properties via a trans-differentiation process, and regulate tissue-associated immune compartments under the control of DC-SIGN.