Fractalkine aggravates LPS-induced macrophage activation and acute kidney injury via Wnt/β-catenin signalling pathway

Fractalkine (CX3CL1, FKN), a CX3C gene sequence inflammatory chemokine, has been found to have pro-inflammatory and pro-adhesion effects. Macrophages are immune cells with a critical role in regulating the inflammatory response. The imbalance of M1/M2 macrophage polarization can lead to aggravated inflammation. This study attempts to investigate the mechanisms through which FKN regulates macrophage activation and the acute kidney injury (AKI) involved in inflammatory response induced by lipopolysaccharide (LPS) by using FKN knockout (FKN-KO) mice and cultured macrophages. It was found that FKN and Wnt/β-catenin signalling have a positive interaction in macrophages. FKN overexpression inhibited LPS-induced macrophage apoptosis. However, it enhanced their cell viability and transformed them into the M2 type. The effects of FKN overexpression were accelerated by activation of Wnt/β-catenin signalling. In the in vivo experiments, FKN deficiency suppressed macrophage activation and reduced AKI induced by LPS. Inhibition of Wnt/β-catenin signalling and FKN deficiency further mitigated the pathologic process of AKI. In summary, we provide a novel mechanism underlying activation of macrophages in LPS-induced AKI. Although LPS-induced murine AKI was unable to completely recapitulate human AKI, the positive interactions between FKN and Wnt/β-catenin signalling pathway may be a therapeutic target in the treatment of kidney injury.     

Methamphetamine-induced neurotoxicity and microglial activation are not mediated by fractalkine receptor signaling

Methamphetamine (METH) damages dopamine (DA) nerve endings by a process that has been linked to microglial activation but the signaling pathways that mediate this response have not yet been delineated. Cardona et al. [Nat. Neurosci. 9 (2006), 917] recently identified the microglial-specific fractalkine receptor (CX3CR1) as an important mediator of MPTP-induced neurodegeneration of DA neurons. Because the CNS damage caused by METH and MPTP is highly selective for the DA neuronal system in mouse models of neurotoxicity, we hypothesized that the CX3CR1 plays a role in METH-induced neurotoxicity and microglial activation. Mice in which the CX3CR1 gene has been deleted and replaced with a cDNA encoding enhanced green fluorescent protein (eGFP) were treated with METH and examined for striatal neurotoxicity. METH depleted DA, caused microglial activation, and increased body temperature in CX3CR1 knockout mice to the same extent and over the same time course seen in wild-type controls. The effects of METH in CX3CR1 knockout mice were not gender-dependent and did not extend beyond the striatum. Striatal microglia expressing eGFP constitutively show morphological changes after METH that are characteristic of activation. This response was restricted to the striatum and contrasted sharply with unresponsive eGFP-microglia in surrounding brain areas that are not damaged by METH. We conclude from these studies that CX3CR1 signaling does not modulate METH neurotoxicity or microglial activation. Furthermore, it appears that striatal-resident microglia respond to METH with an activation cascade and then return to a surveying state without undergoing apoptosis or migration.     

Cellular interplay in pulmonary arterial hypertension: Implications for new therapies

Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by vascular remodeling, vasoconstriction, inflammation and thrombosis. Although the available therapies have resulted in improvements in morbidity and survival, PAH remains a severe and devastating disease with a poor prognosis and a high mortality, justifying the need of novel therapeutic targets. An increasing number of studies have demonstrated that endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts of the pulmonary vessel wall, as well as platelets and inflammatory cells have a role in PAH pathogenesis. This review aims to integrate the interplay among different types of cells, during PAH development and progression, and the impact of current therapies in cellular modulation. The interplay among endothelial cells, smooth muscle cells and fibroblasts present in pulmonary vessels wall, platelets and inflammatory cells is regulated by several mediators produced by these cells, contributing to the pathophysiologic features of PAH. Current therapies are mainly focused in the pulmonary vascular tone and in the endothelial dysfunction. However, once they have not been effective, novel therapies targeting other PAH features, such as inflammation and platelet dysfunction are emerging. Further understanding of the interplay among different vascular cell types involved in PAH development and progression can contribute to find novel therapeutic targets, decreasing PAH mortality and morbidity in the future.     

Fractalkine/CX3CR1 induces apoptosis resistance and proliferation through the activation of the AKT/NF‐κB cascade in pancreatic cancer cells

Fractalkine (FKN, CX3CL1) is highly expressed in a majority of malignant solid tumours. Fractalkine is the only known ligand for CX3CR1. In this study, we performed an analysis to determine the effects of fractalkine/CX3CR1 on modulating apoptosis and explored the related mechanisms. The expression of fractalkine/CX3CR1 was detected by immunohistochemistry and western blotting. The levels of AKT/p‐AKT, BCL‐xl, and BCL‐2 were detected by western blotting. Then, the effects of exogenous and endogenous fractalkine on the regulation of tumour apoptosis and proliferation were investigated. The mechanism of fractalkine/CX3CR1 on modulating apoptosis in cancer cells through the activation of AKT/NF‐κB/p65 signals was evaluated. The effect of fractalkine on regulating cell cycle distribution was also tested. Fractalkine, AKT/p‐AKT, and apoptotic regulatory proteins BCL‐xl and BCL‐2 were highly expressed in human pancreatic cancer tissues. In vitro, fractalkine/CX3CR1 promoted proliferation and mediated resistance to apoptosis in pancreatic cancer cells. The antiapoptotic effect of fractalkine was induced by the activation of AKT/NF‐κB/p65 signalling in pancreatic cancer cells. The NF‐κB/p65 contributes to promote the expressions of BCL‐xl and BCL‐2 and reduce caspase activity, thereby inhibiting apoptotic processes. Treatment with fractalkine resulted in the enrichment of pancreatic cancer cells in S phase with a concomitant decrease in the number of cells in G1 phase. The present study demonstrated the function of fractalkine in the activation of the AKT/NF‐κB/p65 signalling cascade and mediation of apoptosis resistance in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as a diagnostic marker and as a potential target for chemotherapy in early stage pancreatic cancer. Pancreatic cancer is characterized by local recurrence, neural invasion, or distant metastasis. The present study demonstrated the overexpression of fractalkine/CX3CR1 in pancreatic cancer tissues, indicating its important role in the tumourigenesis of pancreatic cancer, and suggested that the overexpression of fractalkine/CX3CR1 could serve as a diagnostic marker for pancreatic cancer. Moreover, we reveal the mechanism that fractalkine functions on the activation of the AKT/NF‐κB/p65 signalling cascade and regulation of the antiapoptosis process in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as an effective therapeutic target of chemotherapeutic and biologic agents in early stage pancreatic cancer.