The role of proinflammatory cytokines and CXC chemokines (CXCL1-CXCL16) in the progression of prostate cancer: insights on their therapeutic management.

Reproductive cancers are malignancies that develop in the reproductive organs. One of the leading cancers affecting the male reproductive system on a global scale is prostate cancer (PCa). The negative consequences of PCa metastases endure and are severe, significantly affecting mortality and life quality for those who are affected. The association between inflammation and PCa has captured interest for a while. Inflammatory cells, cytokines, CXC chemokines, signaling pathways, and other elements make up the tumor microenvironment (TME), which is characterized by inflammation. Inflammatory cytokines and CXC chemokines are especially crucial for PCa development and prognosis. Cytokines (interleukins) and CXC chemokines such as IL-1, IL-6, IL-7, IL-17, TGF-ß, TNF-α, CXCL1-CXCL6, and CXCL8-CXCL16 are thought to be responsible for the pleiotropic effects of PCa, which include inflammation, progression, angiogenesis, leukocyte infiltration in advanced PCa, and therapeutic resistance. The inflammatory cytokine and CXC chemokines systems are also promising candidates for PCa suppression and immunotherapy. Therefore, the purpose of this work is to provide insight on how the spectra of inflammatory cytokines and CXC chemokines evolve as PCa develops and spreads. We also discussed recent developments in our awareness of the diverse molecular signaling pathways of these circulating cytokines and CXC chemokines, as well as their associated receptors, which may one day serve as PCa-targeted therapies. Moreover, the current status and potential of theranostic PCa therapies based on cytokines, CXC chemokines, and CXC receptors (CXCRs) are examined.

Dual roles of HK3 in regulating the network between tumor cells and tumor-associated macrophages in neuroblastoma.

Neuroblastoma (NB) is the most common and deadliest extracranial solid tumor in children. Targeting tumor-associated macrophages (TAMs) is a strategy for attenuating tumor-promoting states. The crosstalk between cancer cells and TAMs plays a pivotal role in mediating tumor progression in NB. The overexpression of Hexokinase-3 (HK3), a pivotal enzyme in glucose metabolism, has been associated with poor prognosis in NB patients. Furthermore, it correlates with the infiltration of M2-like macrophages within NB tumors, indicating its significant involvement in tumor progression. Therefore, HK3 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration, and invasion, but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis in neuroblastoma. The secretion of lactate and histone lactylation alterations within tumor cells accompanies this interaction. Additionally, elevated expression of HK3 in M2-TAMs was found at the same time. Modulating HK3 within M2-TAMs alters the biological behavior of tumor cells, as demonstrated by our in vitro studies. This study highlights the pivotal role of HK3 in the progression of NB malignancy and its intricate regulatory network with M2-TAMs. It establishes HK3 as a promising dual-functional biomarker and therapeutic target in combating neuroblastoma.

The p21+ perinecrotic hepatocytes produce the chemokine CXCL14 after a severe acetaminophen overdose promoting hepatocyte injury and delaying regeneration.

Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available single-nuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as CXCL14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, CXCL14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or CXCL14 with a neutralizing antibody. We found that targeting CXCL14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting senescent hepatocytes had no effect. These data support the conclusion that the sustained induction of p21 in hepatocytes with persistent CXCL14 secretion are critical mechanistic events leading to ALF in mice and human patients.

The Role of CXCL11 and its Receptors in Cancer: Prospective but Challenging Clinical Targets.

Chemokine ligand 11 is a member of the CXC chemokine family and exerts its biological function mainly through binding to CXCR3 and CXCR7. The CXCL11 gene is ubiquitously overexpressed in various human malignant tumors; however, its specific mechanisms vary among different cancer types. Recent studies have found that CXCL11 is involved in the activation of multiple oncogenic signaling pathways and is closely related to tumorigenesis, progression, chemotherapy tolerance, immunotherapy efficacy, and poor prognosis. Depending on the specific expression of its receptor subtype, CXCL11 also has a complex 2-fold role in tumours; therefore, directly targeting the structure-function of CXCL11 and its receptors may be a challenging task. In this review, we summarize the biological functions of CXCL11 and its receptors and their roles in various types of malignant tumors and point out the directions for clinical applications.

CXCL11 is found in many types of cancer and affects how cancer cells grow and respond to treatments. This paper delves into the intricate dance between CXCL11 and its receptors in various types of cancer. Like a versatile actor playing different roles on stage, CXCL11 can either promote or hinder cancer growth depending on its interaction with specific receptors. Understanding how CXCL11 works could help develop new treatments for cancer, but it's a complex challenge because CXCL11 can have different effects depending on the type of cancer and which receptors it binds to.

CXCL17 is an allosteric inhibitor of CXCR4 through a mechanism of action involving glycosaminoglycans.

CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)-based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.

Comprehensive analysis of the clinical and biological significances for chemokine CXCL3 in cholangiocarcinoma.

Cholangiocarcinoma (CHOL) is a race malignant cancer arising from bile duct epithelial cells in clinical practice. C-X-C motif chemokine ligand 3 (CXCL3) is a member of chemokines family, which participates in the pathogenesis of various tumors. However, the association between CXCL3 and CHOL is unclear. This present study was to assess the role of CXCL3 expression in the progress of CHOL. TIMER, GEPIA, UALCAN, GSCA, LinkedOmics, Metascape and STRING databases were performed to evaluate the clinical and biological significances for CXCL3 with CHOL patients including expression, clinicopathological factors, immune cell infiltration, GO enrichment and KEGG pathway analyses, as well as PPI network analysis. The immunohistochemistry analysis of tissue microarray was conducted to detect the protein expression level, subcellular localization, clinicopathological factors and prognosis of CXCL3 in CHOL. The mRNA and protein expression levels of CXCL3 were markedly increased in CHOL tissues. The overexpression of CXCL3 was strongly associated with maximum tumor diameter of patients with CHOL. Additionally, there were negative correlations between the expression of CXCL3 and monocyte as well as Th17. Low infiltration of neutrophil indicated significantly shorter cumulative survival in CHOL patients. And CXCL3 was significantly associated with arm-level deletion of CD8+ T cell. Furthermore, functional network analysis suggested that CXCL3 and its associated genes were mainly enriched for chemotaxis, secretory granule membrane, cytokine activity and IL-17 signaling pathway. CXCL3 might potentially participate in the carcinogenesis of CHOL, which provided a direction for future research on the mechanism of CXCL3 in CHOL.

Structural insights into the activation and inhibition of CXC chemokine receptor 3.

The chemotaxis of CD4+ type 1 helper cells and CD8+ cytotoxic lymphocytes, guided by interferon-inducible CXC chemokine 9-11 (CXCL9-11) and CXC chemokine receptor 3 (CXCR3), plays a critical role in type 1 immunity. Here we determined the structures of human CXCR3-DNGi complexes activated by chemokine CXCL11, peptidomimetic agonist PS372424 and biaryl-type agonist VUF11222, and the structure of inactive CXCR3 bound to noncompetitive antagonist SCH546738. Structural analysis revealed that PS372424 shares a similar orthosteric binding pocket to the N terminus of CXCL11, while VUF11222 buries deeper and activates the receptor in a distinct manner. We showed an allosteric binding site between TM5 and TM6, accommodating SCH546738 in the inactive CXCR3. SCH546738 may restrain the receptor at an inactive state by preventing the repacking of TM5 and TM6. By revealing the binding patterns and the pharmacological properties of the four modulators, we present the activation mechanisms of CXCR3 and provide insights for future drug development.

Osteosarcoma Cells Secrete CXCL14 That Activates Integrin α11ß1 on Fibroblasts to Form a Lung Metastatic Niche.

Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11ß1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFß and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11ß1 axis inhibited fibroblast TGFß production, enhanced CD8+ T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11ß1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. SIGNIFICANCE: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11ß1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.

Involvement of CXC chemokines (CXCL1-CXCL17) in gastric cancer: Prognosis and therapeutic molecules.

Gastric cancer (GC) is the fifth-most prevalent and second-most deadly cancer worldwide. Due to the late onset of symptoms, GC is frequently treated at a mature stage. In order to improve the diagnostic and clinical decision-making processes, it is necessary to establish more specific and sensitive indicators valuable in the early detection of the disease whenever a cancer is asymptomatic. In this work, we gathered information about CXC chemokines and GC by using scientific search engines including Google Scholar, PubMed, SciFinder, and Web of Science. Researchers believe that GC chemokines, small proteins, class CXC chemokines, and chemokine receptors promote GC inflammation, initiation, and progression by facilitating angiogenesis, tumor transformation, invasion, survival, metastatic spread, host response safeguards, and inter-cell interaction. With our absolute best professionalism, the role of CXC chemokines and their respective receptors in GC diagnosis and prognosis has not been fully explained. This review article updates the general characteristics of CXC chemokines, their unique receptors, their function in the pathological process of GC, and their potential application as possible indicators for GC. Although there have only recently been a few studies focusing on the therapeutic efficacy of CXC chemokine inhibitors in GC, growing experimental evidence points to the inhibition of CXC chemokines as a promising targeted therapy. Therefore, further translational studies are warranted to determine whether specific antagonists or antibodies designed to target CXC chemokines alone or in combination with chemotherapy are useful for diagnosing advanced GC.

CXCL17 binds efficaciously to glycosaminoglycans with the potential to modulate chemokine signaling.

Introduction: CXCL17 is a mucosally secreted protein, and the most recently identified human chemokine, an assignment based on protein fold prediction and chemotactic activity for leukocytes. However, these credentials have been the subject of much recent discussion and no experimental evidence has been presented regarding the definitive structure of CXCL17. In this study, we evaluated the structural and chemoattractant credentials of CXCL17 to better characterize this molecule, and gain deeper insights into its functional role as a glycosaminoglycan (GAG) binding protein. Methods: In the absence of structural information, in silico modeling techniques assessed the likelihood of CXCL17 adopting a chemokine fold. Recombinant CXCL17 was synthesized in mammalian and prokaryotic systems. Modified Boyden chamber and real-time chemotaxis assays assessed the ability of CXCL17 to promote chemotaxis of murine splenocytes, human neutrophils, and CXCR1 transfectants. The efficacy of CXCL17 binding to GAGs was quantified with solid-phase assays and bio-layer interferometry techniques. Results: All modeling efforts failed to support classification of CXCL17 as a chemokine based on its predicted conformation. Recombinant CXCL17 was observed to dimerize as a function of concentration, a characteristic of several chemokines. Contrary to a previous report, CXCL17 was not chemotactic for murine splenocytes, although it was a low-potency chemoattractant for human neutrophils at micromolar concentrations, several orders of magnitude higher than those required for CXCL8. As anticipated owing to its highly basic nature, CXCL17 bound to GAGs robustly, with key C-terminal motifs implicated in this process. While inactive via CXCR1, CXCL17 was found to inhibit CXCR1-mediated chemotaxis of transfectants to CXCL8 in a dose-dependent manner. Discussion: In summary, despite finding little evidence for chemokine-like structure and function, CXCL17 readily bound GAGs, and could modulate chemotactic responses to another chemokine in vitro. We postulate that such modulation is a consequence of superior GAG binding, and that C-terminal fragments of CXCL17 may serve as prototypic inhibitors of chemokine function.

Elevated expression of CXCL3 in colon cancer promotes malignant behaviors of tumor cells in an ERK-dependent manner.

BACKGROUND: CXC chemokine ligand 3 (CXCL3) is a member of CXC-type chemokine family that is identified as a major regulator in immune and inflammation responses. Recently, numerous evidence indicated that CXCL3 is broadly expressed in various human tumor types, and it is also known to play a critical role in mediating tumor development and progression. However, the expression profile of CXCL3 and the exact molecular mechanism behind the role of CXCL3 in colon adenocarcinoma (COAD) has not been fully elucidated. METHODS: The expression and clinical significance of CXCL3 mRNA and protein in the tissues from COAD patients were estimated using bioinformatics and immunohistochemistry assays. The expression and roles of exogenous administration or overexpression of CXCL3 in HT-29 and SW480 COAD cells were determined using enzyme-linked immunosorbent assay(ELISA), Cell Counting Kit-8 (CCK-8) and Transwell assays. Mechanically, CXCL3-induced malignant behaviors were elucidated using western blotting assay and extracellular signal-regulated protein kinase 1/2 (ERk1/2) inhibitor PD98059. RESULTS: The cancer genome atlas (TCGA)-COAD data analysis revealed that CXCL3 mRNA is highly expressed and has high clinical diagnostic accuracy in COAD. Increased expression of CXCL3 mRNA was associated with patient's clinical stage, race, gender, age, histological subtype, nodal mestastasis and tumor protein 53 (TP53) mutation status. Similarly, immunohistochemistry assay also exhibited that CXCL3 protein in COAD tissues was significantly up-regulated. Gene expression associated assay implied that CXC chemokine ligand 1 (CXCL1) and CXC chemokine ligand 2 (CXCL2) were markedly correlated with CXCL3 in COAD. Protein-protein interaction (PPI) analysis revealed that cyclin B1 (CCNB1), mitotic arrest deficient 2 like 1 (MAD2L1), H2A family member Z (H2AFZ) and CXCL2 may be the important protein molecules involved in CXCL3-related tumor biology. Gene set enrichment analysis (GSEA) analysis revealed that CXCL3 was mainly enriched in the cell cycle, DNA replication, NOD-like receptors, NOTCH and transforming growth factor-ß (TGF-ß) Signal pathways. In vitro, exogenous administration or overexpression of CXCL3 resulted in increased malignant behaviors of HT-29 and SW480 cells, and down-regulation of CXCL3 expression inhibited the malignant behaviors of these tumor cells. In addition, overexpression of CXCL3 affected the expression of genes related to extracellular signal regulated kinase (ERK) pathway, including ERK1/2, p-ERK, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and Cyclin D1. Finally, CXCL3-induced malignant behaviors in HT-29 and SW480 cells were obviously attenuated following treatment with ERK inhibitor PD98059. CONCLUSION: CXCL3 is upregulated in COAD and plays a crucial role in the control of malignant behaviors of tumor cells, which indicated its involvement in the pathogenesis of COAD.

Bioinformatic Analysis of the CXCR2 Ligands in Cancer Processes.

Human CXCR2 has seven ligands, i.e., CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8/IL-8-chemokines with nearly identical properties. However, no available study has compared the contribution of all CXCR2 ligands to cancer progression. That is why, in this study, we conducted a bioinformatic analysis using the GEPIA, UALCAN, and TIMER2.0 databases to investigate the role of CXCR2 ligands in 31 different types of cancer, including glioblastoma, melanoma, and colon, esophageal, gastric, kidney, liver, lung, ovarian, pancreatic, and prostate cancer. We focused on the differences in the regulation of expression (using the Tfsitescan and miRDB databases) and analyzed mutation types in CXCR2 ligand genes in cancers (using the cBioPortal). The data showed that the effect of CXCR2 ligands on prognosis depends on the type of cancer. CXCR2 ligands were associated with EMT, angiogenesis, recruiting neutrophils to the tumor microenvironment, and the count of M1 macrophages. The regulation of the expression of each CXCR2 ligand was different and, thus, each analyzed chemokine may have a different function in cancer processes. Our findings suggest that each type of cancer has a unique pattern of CXCR2 ligand involvement in cancer progression, with each ligand having a unique regulation of expression.

Comprehensive analysis of CXCL14 uncovers its role during liver metastasis in colon cancer.

BACKGROUND: The most common cause of death for colon cancer patients is liver metastasis. METHODS: All the data enrolled in this study were downloaded from two public databases, The Cancer Genome Atlas Program, the TCGA-COAD project and Gene Expression Omnibus, GSE41258 project. All the analysis was performed in R software. RESULTS: In our study, we systematically explored the molecules involved in the liver metastasis process of colon cancer. The biological role of these molecules was identified through the GO and KEGG analysis. Moreover, we identified that the molecules SERPINA3, SERPINA1, MMP3, ALDH1A3, PBK and CXCL14 were the independent factors for patients survival. The CXCL14 was selected for further analysis for its most significant P value. Single-cell analysis showed that the CXCL14 was mainly expressed in the fibroblasts. Meanwhile, the biological role of fibroblasts in the colon cancer microenvironment was investigated. Further, the clinical role of CXCL14 in colon cancer was also explored. The result showed that the CXCL14 is a protective factor against colon cancer independent of other clinical parameters like age, gender, clinical stage, and TNM classifications. Then, biological enrichment analysis indicated that the CXCL14 is predominantly involved in the activating of the WNT/ß/catenin pathway, pancreas beta cells, peroxisome and bile acid metabolism. Immune infiltration analysis showed that for the patients with high CXCL14 levels, the plasma B cells, CD8 + T cells, neutrophil and NK cells might infiltrate more, in contrast to B cells, monocyte and macrophages. Furthermore, we found that the patients with low CXCL14 expression might be more sensitive to etoposide, rapamycin and sunitinib. CONCLUSIONS: Our result could improve the understanding of the liver metastasis process in colon cancer. Also, CXCL14 was identified as an underlying therapeutic target for colon cancer.

1,5-AG suppresses pro-inflammatory polarization of macrophages and promotes the survival of B-ALL in vitro by upregulating CXCL14.

B-lineage acute lymphoblastic leukemia (B-ALL) is one of the most common malignancies in children. Despite advances in treatment, the role of the tumor microenvironment in B-ALL remains poorly understood. Among the key components of the immune microenvironment, macrophages play a critical role in the progression of the disease. However, recent research has suggested that abnormal metabolites may influence the function of macrophages, altering the immune microenvironment and promoting tumor growth. Our previous non-targeted metabolomic detection revealed that the metabolite 1,5-anhydroglucitol (1,5-AG) level in the peripheral blood of children newly diagnosed with B-ALL was significantly elevated. Except for its direct influence on leukemia cells, the effect of 1,5-AG on macrophages is still unclear. Herein, we demonstrated new potential therapeutic targets by focusing on the effect of 1,5-AG on macrophages. We used polarization-induced macrophages to determine how 1,5-AG acted on M1-like polarization and screened out the target gene CXCL14 via transcriptome sequencing. Furthermore, we constructed CXCL14 knocked-down macrophages and a macrophage-leukemia cell coculture model to validate the interaction between macrophages and leukemia cells. We discovered that 1,5-AG upregulated the CXCL14 expression, thereby inhibiting M1-like polarization. CXCL14 knockdown restored the M1-like polarization of macrophages and induced leukemia cells apoptosis in the coculture model. Our findings offer new possibilities for the genetic engineering of human macrophages to rehabilitate their immune activity against B-ALL in cancer immunotherapy.

CINC-2 and miR-199a-5p in EVs secreted by transplanted Thy1+ cells activate hepatocytic progenitor cell growth in rat liver regeneration.

BACKGROUND: Small hepatocyte-like progenitor cells (SHPCs) are hepatocytic progenitor cells that transiently form clusters in rat livers treated with retrorsine (Ret) that underwent 70% partial hepatectomy (PH). We previously reported that transplantation of Thy1+ cells obtained from D-galactosamine-treated livers promotes SHPC expansion, thereby accelerating liver regeneration. Extracellular vesicles (EVs) secreted by Thy1+ cells induce sinusoidal endothelial cells (SECs) and Kupffer cells (KCs) to secrete IL17B and IL25, respectively, thereby activating SHPCs through IL17 receptor B (RB) signaling. This study aimed to identify the inducers of IL17RB signaling and growth factors for SHPC proliferation in EVs secreted by Thy1+ cells (Thy1-EVs). METHODS: Thy1+ cells isolated from the livers of rats treated with D-galactosamine were cultured. Although some liver stem/progenitor cells (LSPCs) proliferated to form colonies, others remained as mesenchymal cells (MCs). Thy1-MCs or Thy1-LSPCs were transplanted into Ret/PH-treated livers to examine their effects on SHPCs. EVs were isolated from the conditioned medium (CM) of Thy1-MCs and Thy1-LSPCs. Small hepatocytes (SHs) isolated from adult rat livers were used to identify factors regulating cell growth in Thy1-EVs. RESULTS: The size of SHPC clusters transplanted with Thy1-MCs was significantly larger than that of SHPC clusters transplanted with Thy1-LSPCs (p = 0.02). A comprehensive analysis of Thy1-MC-EVs revealed that miR-199a-5p, cytokine-induced neutrophil chemoattractant-2 (CINC-2), and monocyte chemotactic protein 1 (MCP-1) were candidates for promoting SHPC growth. Additionally, miR-199a-5p mimics promoted the growth of SHs (p = 0.02), whereas CINC-2 and MCP-1 did not. SECs treated with CINC-2 induced Il17b expression. KCs treated with Thy1-EVs induced the expression of CINC-2, Il25, and miR-199a-5p. CM derived from SECs treated with CINC-2 accelerated the growth of SHs (p = 0.03). Similarly, CM derived from KCs treated with Thy1-EVs and miR-199a-5p mimics accelerated the growth of SHs (p = 0.007). In addition, although miR-199a-overexpressing EVs could not enhance SHPC proliferation, transplantation of miR-199a-overexpressing Thy1-MCs could promote the expansion of SHPC clusters. CONCLUSION: Thy1-MC transplantation may accelerate liver regeneration owing to SHPC expansion, which is induced by CINC-2/IL17RB signaling and miR-199a-5p via SEC and KC activation.

Geniposide ameliorates atherosclerosis by regulating macrophage polarization via perivascular adipocyte-derived CXCL14.

ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia jasminoides Ellis is a traditional Chinese medicine that has been used for treatment of various diseases, including atherosclerosis by clearing heat and detoxication. Geniposide is considered as the effective compounds responsible for the therapeutic efficacy of Gardenia jasminoides Ellis against atherosclerosis. AIM OF THE STUDY: To investigate the effect of geniposide on atherosclerosis burden and plaque macrophage polarization, with focus on its potential impact on CXCL14 expression by perivascular adipose tissue (PVAT). MATERIALS AND METHODS: ApoE-/- mice fed a western diet (WD) were used to model atherosclerosis. In vitro cultures of mouse 3T3-L1 preadipocytes and RAW264.7 macrophages were used for molecular assays. RESULTS: The results revealed that geniposide treatment reduced atherosclerotic lesions in ApoE-/- mice, and this effect was correlated with increased M2 and decreased M1 polarization of plaque macrophages. Of note, geniposide increased the expression of CXCL14 in PVAT, and both the anti-atherosclerotic effect of geniposide, as well as its regulatory influence on macrophage polarization, were abrogated upon in vivo CXCL14 knockdown. In line with these findings, exposure to conditioned medium from geniposide-treated 3T3-L1 adipocytes (or to recombinant CXCL14 protein) enhanced M2 polarization in interleukin-4 (IL-4) treated RAW264.7 macrophages, and this effect was negated after CXCL14 silencing in 3T3-L1 cells. CONCLUSION: In summary, our findings suggest that geniposide protects ApoE-/- mice against WD-induced atherosclerosis by inducing M2 polarization of plaque macrophages via enhanced expression of CXCL14 in PVAT. These data provide novel insights into PVAT paracrine function in atherosclerosis and reaffirm geniposide as a therapeutic drug candidate for atherosclerosis treatment.

What defines a chemokine? - The curious case of CXCL17.

Chemotactic cytokines (chemokines) are a group of around 40 small proteins which share a similar protein fold and are well known for their ability to direct the migration of leukocytes to a variety of tissue locations. CXCL17 was the last member of the chemokine family to be assigned and was admitted to the family based on theoretical modelling of the CXCL17 structure and chemotactic activity for monocytes and dendritic cells. Of Interest, CXCL17 expression appears to be restricted to mucosal tissues such as the tongue, stomach and lung, suggestive of specific roles at these locations. A putative CXCL17 receptor, GPR35 was reportedly identified and mice deficient in CXCL17 were generated and characterised. More recently, however, some apparent contradictions regarding aspects of CXCL17 biology have been raised by ourselves and others. Notably, GPR35 appears to be a receptor for the serotonin metabolite 5-hydroxyindoleacetic acid rather than for CXCL17 and modelling of CXCL17 using a variety of platforms fails to identify a chemokine-like fold. In this article, we summarize the discovery of CXCL17 and discuss key papers describing the subsequent characterisation of this protein. Ultimately, we pose the question, 'What defines a chemokine?' (185 words).

[Hypoxia promotes lipopolysaccharide-induced CXCL10 expression in microglia].

This study was aimed to investigate the effect of hypoxia on lipopolysaccharide (LPS)-induced CXC-chemokine ligand-10 (CXCL10) expression and the underlying mechanism. C57BL/6J mice were randomly divided into control, hypoxia, LPS, and hypoxia combined with LPS groups. The LPS group was intraperitoneally injected with 0.5 mg/kg LPS, and the hypoxia group was placed in a hypobaric hypoxia chamber (simulated altitude of 6 000 m). The serum and hippocampal tissue samples were collected after 6 h of the treatment. The levels of CXCL10 in the serum and hippocampal tissue of mice were detected by ELISA. The microglia cell line BV2 and primary microglia were stimulated with hypoxia (1% O2) and/or LPS (100 ng/mL) for 6 h. The mRNA expression level of CXCL10 and its content in culture supernatant were detected by real-time quantitative PCR and ELISA, respectively. The phosphorylation levels of nuclear factor κB (NF-κB) signaling pathway-related proteins, p65 and IκBα, were detected by Western blot. Moreover, after NF-κB signaling pathway being blocked with a small molecular compound, PDTC, CXCL10 mRNA expression level was detected in the BV2 cells. The results showed that in the LPS-induced mouse inflammatory model, hypoxia treatment could promote LPS-induced up-regulation of CXCL10 in both serum and hippocampus. Compared with the cells treated with LPS alone, the expression of CXCL10 mRNA and the content of CXCL10 in the culture supernatant of BV2 cells treated with hypoxia combined with LPS were significantly increased. The CXCL10 mRNA level of primary microglial cells treated with hypoxia combined with LPS was significantly up-regulated. Compared with the cells treated with hypoxia or LPS alone, the phosphorylation levels of p65 and IκBα in the BV2 cells treated with hypoxia combined with LPS were significantly increased. PDTC blocked the induction of CXCL10 gene expression by LPS in the BV2 cells. These results suggest that hypoxia promotes LPS-induced expression of CXCL10 in both animal and cell models, and NF-κB signaling pathway plays an important role in this process.

Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option.

Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.

Meteorin-like levels are associated with active brown adipose tissue in early infancy.

Introduction: Meteorin-like (METRNL) is a hormonal factor released by several tissues, including thermogenically active brown and beige adipose tissues. It exerts multiple beneficial effects on metabolic and cardiovascular systems in experimental models. However, the potential role of METRNL as brown adipokine in humans has not been investigated previously, particularly in relation to the metabolic adaptations taking place in early life, when brown adipose tissue (BAT) is particularly abundant. Methods and materials: METRNL levels, as well as body composition (DXA) and circulating endocrine-metabolic variables, were assessed longitudinally in a cohort of infants at birth, and at ages 4 and 12 months. BAT activity was measured by infrared thermography at age 12 months. METRNL levels were also determined cross-sectionally in adults; METRNL gene expression (qRT-PCR) was assessed in BAT and liver samples from neonates, and in adipose tissue and liver samples form adults. Simpson-Golabi-Behmel Syndrome (SGBS) adipose cells were thermogenically activated using cAMP, and METRNL gene expression and METRNL protein released were analysed. Results: Serum METRNL levels were high at birth and declined across the first year of life albeit remaining higher than in adulthood. At age 4 and 12 months, METRNL levels correlated positively with circulating C-X-C motif chemokine ligand 14 (CXCL14), a chemokine released by thermogenically active BAT, but not with parameters of adiposity or metabolic status. METRNL levels also correlated positively with infrared thermography-estimated posterior-cervical BAT activity in girls aged 12 months. Gene expression analysis indicated high levels of METRNL mRNA in neonatal BAT. Thermogenic stimulus of brown/beige adipocytes led to a significant increase of METRNL gene expression and METRN protein release to the cell culture medium. Conclusion: Circulating METRNL levels are high in the first year of life and correlate with indices of BAT activity and with levels of an established brown adipokine such as CXCL14. These data, in addition with the high expression of METRNL in neonatal BAT and in thermogenically-stimulated brown/beige adipocytes, suggest that METRNL is actively secreted by BAT and may be a circulating biomarker of BAT activity in early life.