CX₃CR1 is critical for Salmonella-induced migration of dendritic cells into the intestinal lumen

We have demonstrated that direct antigen sampling of bacteria by intestinal dendritic cells (DCs) is accompanied by a rapid migration of CD11c⁺CX₃CR1⁺MHCII⁺CD8α-CD11b⁻ DCs into the intestinal lumen upon exposure to non-invasive ΔSPI1-Salmonella. Importantly, intraluminal DCs internalized Salmonella but were not able to cross the epithelium to return into tissue, thus showing that these DCs do not function as antigen-presenting cells and participate in the conventional regulation of immune responses to intestinal pathogens. Here we show that the presence of the chemokine receptor CX₃CR1, that plays a vital role in DC-mediated antigen sampling and clearance in the gut, is also instrumental for the transepithelial migration of DCs. The latter observation, along with the notion that CX₃CR1-deficient mice displayed higher susceptibility to Salmonella infection compared to wild-type mice raises the possibility that Salmonella-induced migration of “bacteria-capturing” DCs into the lumen may be an important mechanism of mucosal defence and clearance.Key words: dendritic cell, mucosal immunity, Salmonella, antigen sampling, cell migration, immune exclusion, mucosal clearance     

Sodium selenite ameliorates dextran sulfate sodiuminduced chronic colitis in mice by decreasing Th1, Th17, and γδT and increasing CD4(+)CD25(+) regulatory T-cell responses

AIM To assess the effect of sodium selenite on the severity of dextran sulfate sodium(DSS)-induced colitis in C57BL/6 mice.METHODS Mice were randomly divided into four groups(n = 10/group): normal group, selenium(Se) group, chronic colitis group, and Se + chronic colitis group. The mice were sacrificed on day 26. Survival rates, clinical symptoms, colon length, and histological changes were determined. The percentages and absolute numbers of immune system cells in the lamina propria lymphocytes(LPL) of the colon, the expression of m RNA in colon tissue, and the concentrations of Th1, Th17, and Treg cytokines in LPL from the large intestine, were measured.RESULTS Se significantly ameliorated the symptoms of colitis and histological injury(P 0.05 each), increasing the proportions of neutrophils and CD4+ CD25+ T cells(P 0.05 each) and decreasing the proportions of γδT cells, CD4+, CD4+CD44+, and CD4+ CD69+ T cells in LPL(P 0.05 each). Moreover, Se reduced the expression of IL-6, IFN-γ, IL-17 A, IL-21, T-bet, and RORγt(P 0.05 each), but enhanced the expression of IL-10 and Foxp3(P 0.05 each). CONCLUSION These results suggest that Se protects against DSSinduced chronic colitis perhaps by increasing the number of CD4(+)CD25(+) Tregs that suppress the secretion of proinflammatory cytokines and populations of Th1, Th17, and γδT cells.     

What are CX3CR1+ mononuclear cells in the intestinal mucosa?

Intestinal dendritic cells (DC) and macrophages play a key role for the maintenance of intestinal integrity by initiating innate and adaptive immune responses. Although DC and macrophages have been viewed as distinct lineages, the reliability of surface markers for the definition of DC and macrophages has recently been questioned. Here, I will discuss the ontogeny and function of CX(3)CR1(+) mononuclear cells in the small and large intestine.     

The fractalkine receptor CX₃CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes

Chemokines modulate inflammatory responses that are prerequisites for organ fibrosis upon liver injury. Monocyte-derived hepatic macrophages are critical for the development, maintenance, and resolution of hepatic fibrosis. The specific role of monocyte-associated chemokine (C-X3-C motif) receptor 1 (CX?CR1) and its cognate ligand fractalkine [chemokine (C-X3-C motif) ligand 1)] in liver inflammation and fibrosis is currently unknown. We examined 169 patients with chronic liver diseases and 84 healthy controls; we found that CX?CL1 is significantly up-regulated in the circulation upon disease progression, whereas CX?CR1 is down-regulated intrahepatically in patients with advanced liver fibrosis or cirrhosis. To analyze the functional relevance of this pathway, two models of experimental liver fibrosis were applied to wild-type (WT) and CX?CR1-deficient mice. Fractalkine expression was induced upon liver injury in mice, primarily in hepatocytes and hepatic stellate cells. CX?CR1(-/-) animals developed greater hepatic fibrosis than WT animals with carbon tetrachloride-induced and bile duct ligation-induced fibrosis. CX?CR1(-/-) mice displayed significantly increased numbers of monocyte-derived macrophages within the injured liver. Chimeric animals that underwent bone marrow transplantation revealed that CX?CR1 restricts hepatic fibrosis progression and monocyte accumulation through mechanisms exerted by infiltrating immune cells. In the absence of CX?CR1, intrahepatic monocytes develop preferentially into proinflammatory tumor necrosis factor-producing and inducible nitric oxide synthase-producing macrophages. CX?CR1 represents an essential survival signal for hepatic monocyte-derived macrophages by activating antiapoptotic bcl2 expression. Monocytes/macrophages lacking CX?CR1 undergo increased cell death after liver injury, which then perpetuates inflammation, promotes prolonged inflammatory monocyte infiltration into the liver, and results in enhanced liver fibrosis. CONCLUSION: CX?CR1 limits liver fibrosis in vivo by controlling the differentiation and survival of intrahepatic monocytes. The opposing regulation of CX?CR1 and fractalkine in patients suggests that pharmacological augmentation of this pathway may represent a possible therapeutic antifibrotic strategy.     

Tartrate-resistant acid phosphatase-positive cells in the synovial–cartilage junction and bone marrow during the progression of collagen-induced arthritis in adult rats

We investigated the time-course changes in bone destruction in rats with collagen-induced arthritis (CIA). The synovial–cartilage junction (SCJ) and epiphyseal bone marrow of the femoral posteromedial condyle in CIA rats were evaluated histologically and immunohistologically at 2, 3, 4, 6, and 8 weeks after sensitization. Two weeks after sensitization, tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells formed resorption lacunae on the lateral side of the cortical bone under the SCJ. No resorption lacunae were observed in bone marrow. Three weeks after sensitization, resorption lacunae on the lateral side of the cortical bone expanded, but no bone marrow invasion by pannus was observed. In bone marrow, many TRAP-positive multinuclear cells appeared and formed resorption lacunae in subchondral bone. Four weeks after sensitization, cortical bone was destroyed, and pannus had invaded the bone marrow. After six weeks, trabecular bone and subchondral bone plate were extensively resorbed by TRAP-positive cells. Bone destruction in CIA began with the appearance of TRAP-positive cells on the lateral side of the cortical bone under the SCJ, followed by the TRAP-positive multinuclear cells in bone marrow, which were morphologically unconnected to the SCJ lesions. These histological findings suggested that bone destruction in the early stage of arthritis occurred in two anatomically different regions.     

Oxidative stress induces loss of pericyte coverage and vascular instability in PGC-1α-deficient mice

Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) is a regulator of mitochondrial oxidative metabolism and reactive oxygen species (ROS) homeostasis that is known to be inactivated in diabetic subjects. This study aimed to investigate the contribution of PGC-1α inactivation to the development of oxygen-induced retinopathy. We analyzed retinal vascular development in PGC-1α^?/? mice. Retinal vasculature of PGC-1α^?/? mice showed reduced pericyte coverage, a de-structured vascular plexus, and low perfusion. Exposure of PGC-1α^?/? mice to hyperoxia during retinal vascular development exacerbated these vascular abnormalities, with extensive retinal hemorrhaging and highly unstructured areas as compared with wild-type mice. Structural analysis demonstrated a reduction in membrane-bound VE-cadherin, which was suggestive of defective intercellular junctions. Interestingly, PGC-1α^?/? retinas showed a constitutive activation of the VEGF-A signaling pathway. This phenotype could be partially reversed by antioxidant administration, indicating that elevated production of ROS in the absence of PGC-1α could be a relevant factor in the alteration of the VEGF-A signaling pathway. Collectively, our findings suggest that PGC-1α control of ROS homeostasis plays an important role in the regulation of de novo angiogenesis and is required for vascular stability.     

Chemokine–Chemokine Receptor CCL2–CCR2 and CX3CL1–CX3CR1 Axis May Play a Role in the Aggravated Inflammation in Primary Biliary Cirrhosis

Background and Aims

Senescent cells can alter local tissue environments by secretion of various senescence-associated secretory phenotypes (SASP), such as cytokines and chemokines. Given senescent biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show increased expression of chemokines CCL2 and CX3CL1 as SASP, we further examined an involvement of CCL2/CCR2 and CX3CL1/CX3CR1 systems in the pathogenesis of PBC.

Methods

We examined immunohistochemically the expression of CCR2, CX3CR1, CCL2 and CX3CL1 in livers taken from the patients with PBC (n = 45) and control livers (n = 78), such as chronic viral hepatitis (CVH; n = 39). CCR2 or CX3CR1-expressing cells were characterized by double immunofluorescence with CD3, CD4, CD8, CD56 or CD68.

Results

CCR2 is expressed in round cells, epithelioid cells and dendritic cells and most CCR2-positive cells were CD68-positive. Infiltration of CCR2-positive cells in the intraepithelial layer or around small bile ducts was significantly more extensive in PBC than CVH and normal liver (p < 0.05) and was significantly correlated with the expression of CCL2 in BECs (p < 0.01). Most CX3CR1-expressing inflammatory cells were CD3-positive T cells (CD8 > CD4). Infiltration of CX3CR1-positive cells in the intraepithelial layer and around small bile ducts was significantly more extensive in PBC than control livers (p < 0.05) and was significantly correlated with the expression of CX3CL1 in BECs (p < 0.05).

Conclusion

CCL2 and CX3CL1 produced by senescent BECs may promote infiltration of corresponding CCR2 and CX3CR1-expressing cells and further aggravate inflammation in bile duct lesion in PBC.     

What are CX3CR1+ mononuclear cells in the intestinal mucosa?

Intestinal dendritic cells (DC) and macrophages play a key role for the maintenance of intestinal integrity by initiating innate and adaptive immune responses. Although DC and macrophages have been viewed as distinct lineages, the reliability of surface markers for the definition of DC and macrophages has recently been questioned. Here, I will discuss the ontogeny and function of CX₃CR1⁺ mononuclear cells in the small and large intestine.     

The effect of qinghaosu on PFC and RFC responses in the mice infected with Plasmodium berghei.

Qinghaosu was given to mice infected with P. berghei at the time when the para-sitaemia was 30% and when the PFC and RFC responses of the infected mice weremuch lower than those of the healthy ones. The dose given was 300 mg/kg in 7 days.The mice were immunized with sheep erythrocyte on day 0, 7, 14, 21 respectively