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.

CXCL3: A key player in tumor microenvironment and inflammatory diseases.

CXCL3 (C-X-C Motif Chemokine 3), a member of the C-X-C chemokine subfamily, operates as a potent chemoattractant for neutrophils, thereby orchestrating the recruitment and migration of leukocytes alongside eliciting an inflammatory response. Recent inquiries have shed light on the pivotal roles of CXCL3 in the context of carcinogenesis. In the tumor microenvironment, CXCL3 emanating from both tumor and stromal cells intricately modulates cellular behaviors through autocrine and paracrine actions, primarily via interaction with its receptor CXCR2. Activation of signaling cascades such as ERK/MAPK, AKT, and JAK2/STAT3 underscores CXCL3's propensity to favor tumorigenic processes. However, CXCL3 exhibits dualistic behaviors, as evidenced by its capacity to exert anti-tumor effects under specific conditions. Additionally, the involvement of CXCL3 extends to inflammatory disorders like eclampsia, obesity, and asthma. This review encapsulates the structural attributes, biological functionalities, and molecular underpinnings of CXCL3 across both tumorigenesis and inflammatory diseases.

Pro-inflammatory cytokines and CXC chemokines as game-changer in age-associated prostate cancer and ovarian cancer: Insights from preclinical and clinical studies' outcomes.

Prostate cancer (PC) and Ovarian cancer (OC) are two of the most common types of cancer that affect the reproductive systems of older men and women. These cancers are associated with a poor quality of life among the aged population. Therefore, finding new and innovative ways to detect, treat, and prevent these cancers in older patients is essential. Finding biomarkers for these malignancies will increase the chance of early detection and effective treatment, subsequently improving the survival rate. Studies have shown that the prevalence and health of some illnesses are linked to an impaired immune system. However, the age-associated changes in the immune system during malignancies such as PC and OC are poorly understood. Recent research has suggested that the excessive production of inflammatory immune mediators, such as interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor (TGF), tumor necrosis factor (TNF), CXC motif chemokine ligand 1 (CXCL1), CXC motif chemokine ligand 12 (CXCL12), and CXC motif chemokine ligand 13 (CXCL13), etc., significantly impact the development of PC and OC in elderly patients. Our review focuses on the latest functional studies of pro-inflammatory cytokines (interleukins) and CXC chemokines, which serve as biomarkers in elderly patients with PC and OC. Thus, we aim to shed light on how these biomarkers affect the development of PC and OC in elderly patients. We also examine the current status and future perspective of cytokines (interleukins) and CXC chemokines-based therapeutic targets in OC and PC treatment for elderly patients.

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.

PAX6/CXCL14 regulatory axis promotes the repair of corneal injury by enhancing corneal epithelial cell proliferation.

BACKGROUND: Corneal injuries, often leading to severe vision loss or blindness, have traditionally been treated with the belief that limbal stem cells (LSCs) are essential for repair and homeostasis, while central corneal epithelial cells (CCECs) were thought incapable of such repair. However, our research reveals that CCECs can fully heal and maintain the homeostasis of injured corneas in rats, even without LSCs. We discovered that CXCL14, under PAX6's influence, significantly boosts the stemness, proliferation, and migration of CCECs, facilitating corneal wound healing and homeostasis. This finding introduces CXCL14 as a promising new drug target for corneal injury treatment. METHODS: To investigate the PAX6/CXCL14 regulatory axis's role in CCECs wound healing, we cultured human corneal epithelial cell lines with either increased or decreased expression of PAX6 and CXCL14 using adenovirus transfection in vitro. Techniques such as coimmunoprecipitation, chromatin immunoprecipitation, immunofluorescence staining, western blot, real-time PCR, cell colony formation, and cell cycle analysis were employed to validate the axis's function. In vivo, a rat corneal epithelial injury model was developed to further confirm the PAX6/CXCL14 axis's mechanism in repairing corneal damage and maintaining corneal homeostasis, as well as to assess the potential of CXCL14 protein as a therapeutic agent for corneal injuries. RESULTS: Our study reveals that CCECs naturally express high levels of CXCL14, which is significantly upregulated by PAX6 following corneal damage. We identified SDC1 as CXCL14's receptor, whose engagement activates the NF-κB pathway to stimulate corneal repair by enhancing the stemness, proliferative, and migratory capacities of CCECs. Moreover, our research underscores CXCL14's therapeutic promise for corneal injuries, showing that recombinant CXCL14 effectively accelerates corneal healing in rat models. CONCLUSION: CCECs play a critical and independent role in the repair of corneal injuries and the maintenance of corneal homeostasis, distinct from that of LSCs. The PAX6/CXCL14 regulatory axis is pivotal in this process. Additionally, our research demonstrates that the important function of CXCL14 in corneal repair endows it with the potential to be developed into a novel therapeutic agent for treating corneal injuries.

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.

TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis.

Objective: Osteoarthritis (OA) is the most prominent chronic arthritic disease, affecting over 3 billion people globally. Synovial macrophages, as immune cells, play an essential role in cartilage damage in OA. Therefore, regulating macrophages is crucial for controlling the pathological changes in OA. Triggering receptor expressed on myeloid cells 2 (TREM2), as expressed on immune cell surfaces, such as macrophages and dendritic cells, has suppressed inflammation and regulated M2 macrophage polarization but demonstrated an unknown role in synovial macrophage polarization in OA. This study aimed to investigate TREM2 expression downregulation in OA mice macrophages. Furthermore, the expression trend of TREM2 was associated with polarization-related molecule expression in macrophages of OA mice. Results: We used TREM2 knockout (TREM2-KO) mice to observe that TREM2 deficiency significantly exacerbated the joint inflammation response in OA mice, thereby accelerating disease progression. Separating macrophages and chondrocytes from TREM2-KO mice and co-cultivating them significantly increased chondrocyte apoptosis and inhibited chondrocyte proliferation. Further, TREM2 deficiency also significantly enhanced phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway activation, increasing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 3 (CXCL3) expression. Furthermore, NF-κB signaling pathway inhibition significantly suppressed arthritis inflammation in OA mice, thereby effectively alleviating TREM2 deficiency-related adverse effects on chondrocytes. Notably, knocking down CXCL3 of TREM2-KO mice macrophages significantly inhibits inflammatory response and promotes chondrocyte proliferation. Intravenous recombinant TREM2 protein (soluble TREM2, sTREM2) injection markedly promotes macrophage polarization from M1 to M2 and improves the joint tissue pathology and inflammatory response of OA. Conclusion: Our study reveals that TREM2 promotes macrophage polarization from M1 to M2 during OA by NF-κB/CXCL3 axis regulation, thereby improving the pathological state of OA.

Analysis of the mucosal chemokines CCL28, CXCL14, and CXCL17 in dry eye disease: An in vitro and clinical investigation.

Mucosal chemokines have antimicrobial properties and play an important role in mucosal immunity. However, little is known about their expression on the ocular surface. This study aimed to analyze the expression of the mucosal chemokines CCL28, CXCL14 and CXCL17 in corneal and conjunctival epithelial cells under in vitro dry eye (DE) conditions, and in conjunctival samples from healthy subjects and DE patients. Human corneal epithelial cells (HCE) and immortalized human conjunctival epithelial cells (IM-HConEpiC) were incubated under hyperosmolar (400-500 mOsM) or inflammatory (TNF-α 25 ng/mL) conditions for 6 h and 24 h to measure CCL28, CXCL14, and CXCL17 gene expression by RT-PCR and their secretion by immunobead-based analysis (CCL28, CXCL14) and ELISA (CXCL17). Additionally, twenty-seven DE patients and 13 healthy subjects were included in this study. DE-related questionnaires (OSDI, mSIDEQ and NRS) evaluated symptomatology. Ocular surface integrity was assessed using vital staining. Tactile sensitivity was measured with Cochet-Bonnet esthesiometer, and mechanic and thermal (heat and cold) sensitivity using Belmonte's non-contact esthesiometer. Subbasal nerve plexus and dendritic cell density were analyzed by in vivo confocal microscopy. Conjunctival cells from participants were collected by impression cytology to measure mucosal chemokines gene expression by RT-PCR. Our results showed that HCE and IM-HConEpiC cells increased CCL28, CXCL14, and CXCL17 secretion under hyperosmolar conditions. The gene expression of CCL28 was significantly upregulated in conjunctival samples from DE patients. CCL28 expression correlated positively with symptomatology, corneal staining, heat sensitivity threshold, and dendritic cell density. CXCL14 expression correlated positively with age, ocular pain, conjunctival staining, tactile sensitivity, and image reflectivity. CXCL17 expression correlated positively with corneal staining. These results suggest that corneal and conjunctival epithelial cells could be a source of CCL28, CXCL14, and CXCL17 on the ocular surface and that CCL28 might be involved in DE pathogenesis.

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.

Targeting the CXCL12/CXCR4 pathway to reduce radiation treatment side effects.

High precision, image-guided radiotherapy (RT) has increased the therapeutic ratio, enabling higher tumor and lower normal tissue doses, leading to improved patient outcomes. Nevertheless, some patients remain at risk of developing serious side effects.In many clinical situations, the radiation tolerance of normal tissues close to the target volume limits the dose that can safely be delivered and thus the potential for tumor control and cure. This is particularly so in patients being re-treated for tumor progression or a second primary tumor within a previous irradiated volume, scenarios that are becoming more frequent in clinical practice.Various normal tissue 'radioprotective' drugs with the potential to reduce side effects have been studied previously. Unfortunately, most have failed to impact clinical practice because of lack of therapeutic efficacy, concern about concurrent tumor protection or excessive drug-related toxicity. This review highlights the evidence indicating that targeting the CXCL12/CXCR4 pathway can mitigate acute and late RT-induced injury and reduce treatment side effects in a manner that overcomes these previous translational challenges. Pre-clinical studies involving a broad range of normal tissues commonly affected in clinical practice, including skin, lung, the gastrointestinal tract and brain, have shown that CXCL12 signalling is upregulated by RT and attracts CXCR4-expressing inflammatory cells that exacerbate acute tissue injury and late fibrosis. These studies also provide convincing evidence that inhibition of CXCL12/CXCR4 signalling during or after RT can reduce or prevent RT side effects, warranting further evaluation in clinical studies. Greater dialogue with the pharmaceutical industry is needed to prioritize the development and availability of CXCL12/CXCR4 inhibitors for future RT studies.

CXCL17 is a proinflammatory chemokine and promotes neutrophil trafficking.

CXCL17, a novel member of the CXC chemokine class, has been implicated in several human pathologies, but its role in mediating immune response is not well understood. Characteristic features of immune response include resident macrophages orchestrating successive and structured recruitment of neutrophils and monocytes to the insult site. Here, we show that Cxcl17 knockout (KO) mice, compared with the littermate wild-type control mice, were significantly impaired in peritoneal neutrophil recruitment post-lipopolysaccharide (LPS) challenge. Further, the KO mice show dysregulated Cxcl1, Cxcr2, and interleukin-6 levels, all of which directly impact neutrophil recruitment. Importantly, the KO mice showed no difference in monocyte recruitment post-LPS challenge or in peritoneal macrophage levels in both unchallenged and LPS-challenged mice. We conclude that Cxcl17 is a proinflammatory chemokine and that it plays an important role in the early proinflammatory response by promoting neutrophil recruitment to the insult site.

The Chemokine CXCL14 as a Potential Immunotherapeutic Agent for Cancer Therapy.

There is great enthusiasm toward the development of novel immunotherapies for the treatment of cancer, and given their roles in immune system regulation, chemokines stand out as promising candidates for use in new cancer therapies. Many previous studies have shown how chemokine signaling pathways could be targeted to halt cancer progression. We and others have revealed that the chemokine CXCL14 promotes antitumor immune responses, suggesting that CXCL14 may be effective for cancer immunotherapy. However, it is still unknown what mechanism governs CXCL14-mediated antitumor activity, how to deliver CXCL14, what dose to apply, and what combinations with existing therapy may boost antitumor immune responses in cancer patients. Here, we provide updates on the role of CXCL14 in cancer progression and discuss the potential development and application of CXCL14 as an immunotherapeutic agent.

CXCL14 as a Key Regulator of Neuronal Development: Insights from Its Receptor and Multi-Omics Analysis.

CXCL14 is not only involved in the immune process but is also closely related to neurodevelopment according to its molecular evolution. However, what role it plays in neurodevelopment remains unclear. In the present research, we found that, by crossbreeding CXCL14+/- and CXCL14-/- mice, the number of CXCL14-/- mice in their offspring was lower than the Mendelian frequency; CXCL14-/- mice had significantly fewer neurons in the external pyramidal layer of cortex than CXCL14+/- mice; and CXCL14 may be involved in synaptic plasticity, neuron projection, and chemical synaptic transmission based on analysis of human clinical transcriptome data. The expression of CXCL14 was highest at day 14.5 in the embryonic phase and after birth in the mRNA and protein levels. Therefore, we hypothesized that CXCL14 promotes the development of neurons in the somatic layer of the pyramidal cells of mice cortex on embryonic day 14.5. In order to further explore its mechanism, CXCR4 and CXCR7 were suggested as receptors by Membrane-Anchored Ligand and Receptor Yeast Two-Hybrid technology. Through metabolomic techniques, we inferred that CXCL14 promotes the development of neurons by regulating fatty acid anabolism and glycerophospholipid anabolism.

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.

Proinflammatory chemokine CXCL14 activates MAS-related G protein-coupled receptor MRGPRX2 and its putative mouse ortholog MRGPRB2.

Patients with idiopathic pulmonary fibrosis show a strongly upregulated expression of chemokine CXCL14, whose target is still unknown. Screening of CXCL14 in a panel of human G protein-coupled receptors (GPCRs) revealed its potent and selective activation of the orphan MAS-related GPCR X2 (MRGPRX2). This receptor is expressed on mast cells and - like CXCL14 - upregulated in bronchial inflammation. CXCL14 induces robust activation of MRGPRX2 and its putative mouse ortholog MRGPRB2 in G protein-dependent and ß-arrestin recruitment assays that is blocked by a selective MRGPRX2/B2 antagonist. Truncation combined with mutagenesis and computational studies identified the pharmacophoric sequence of CXCL14 and its presumed interaction with the receptor. Intriguingly, C-terminal domain sequences of CXCL14 consisting of 4 to 11 amino acids display similar or increased potency and efficacy compared to the full CXCL14 sequence (77 amino acids). These results provide a rational basis for the future development of potential idiopathic pulmonary fibrosis therapies.

Identification of Low-Density Lipoprotein Receptor-Related Protein 1 as a CXCL14 Receptor Using Chemically Synthesized Tetrafunctional Probes.

CXCL14 is a primordial CXC-type chemokine that transports CpG oligodeoxynucleotides (ODN) into endosomes and lysosomes in dendritic cells, thereby leading to the activation of the Toll-like receptor 9 (TLR9)-mediated innate immune system. However, the underlying molecular mechanism by which the CXCL14-CpG ODN complex enters cells remains elusive. Herein, we describe the chemical synthesis of CXCL14-derived photoaffinity probes and their application to the identification of target receptors for CXCL14 using quantitative proteomics. By utilizing native chemical ligation and maleimide-thiol coupling chemistry, we synthesized site-specifically modified CXCL14-based photoaffinity probes that contain photoreactive 2-aryl-5-carboxytetrazole (ACT) and a hydrazine-labile cleavable linker. CXCL14-based probes were found to be capable of binding CpG ODN to immune cells, whose bioactivities were comparable to native CXCL14. Application of CXCL14-derived probes to quantitative proteomic experiments enabled the identification of dozens of target receptor candidates for CXCL14 in mouse macrophage-derived RAW264.7 cells, and we discovered that low-density lipoprotein receptor-related protein 1 (LRP1) is a novel receptor for CXCL14 by competitive proteome profiling. We further showed that disruption of LRP1 affected the incorporation of the CXCL14-CpG ODN complex in the cells. Overall, this report highlights the power of synthetic CXCL14-derived photoaffinity probes combined with chemical proteomics to discover previously unidentified receptors for CXCL14, which could promote an understanding of the molecular functions of CXCL14 and the elaborate machinery of innate immune systems.

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.