Explore the vast range of titles available.

The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation, and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor-promoting (Ym1 + , Fizz + , Arg1 + ) phenotype, increases fibrosis, and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.

The chemokine receptor CXCR3 and its ligands (MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11) play a central role in the generation of cellular inflammation, both in the protective responses to invading pathogens, and in different pathological conditions associated with autoimmunity. It is worth noting that CXCR3 is highly expressed on innate and adaptive lymphocytes, as well as on various cell subsets that are localized in non-immune organs and tissues. Our review focuses exclusively on CXCR3-expressing T cells, including Th1, Th17.1, Tfh17, Tfh17.1, CXCR3+ Treg cells, and Tc1 CD8+ T cells. Currently, numerous studies have highlighted the role of CXCR3-dependent interactions in the coordination of inflammation in the peripheral tissues, both to increase recruitment of CD4+ and CD8+ T cells that upregulate inflammation, and also for recruitment of CXCR3+ T regulatory cells to dampen overexuberant responses. Understanding the role of CXCR3 and its ligands might help to apply them as new and effective therapeutic targets in a wide range of diseases.

Chemokine receptors are critically involved in multiple physiological and pathophysiological processes related to immune response mechanisms. Most chemokine receptors are prototypical GPCRs although some also exhibit naturally-encoded signaling-bias toward β-arrestins (βarrs). C-X-C type chemokine receptors, namely CXCR3 and CXCR7, constitute a pair wherein the former is a prototypical GPCR while the latter exhibits selective coupling to βarrs despite sharing a common natural agonist: CXCL11. Moreover, CXCR3 and CXCR7 also recognize small molecule agonists suggesting a modular orthosteric ligand binding pocket. Here, we determine cryo-EM structures of CXCR3 in an Apo-state and in complex with small molecule agonists biased toward G-proteins or βarrs. These structural snapshots uncover an allosteric network bridging the ligand-binding pocket to intracellular side, driving the transducer-coupling bias at this receptor. Furthermore, structural topology of the orthosteric binding pocket also allows us to discover and validate that selected small molecule agonists of CXCR3 display robust agonism at CXCR7. Collectively, our study offers molecular insights into signaling-bias and dual agonism in the CXCR3-CXCR7 system with therapeutic implications. CXCR3 and CXCR7 are chemokine receptors involved in cellular migration in physiological and pathophysiological context. Here, the authors present cryo-EM structures of CXCR3 in complex with small molecule agonists and discover their dual-agonism at CXCR7.

Bystander activation of memory T cells occurs in the absence of cognate antigen during infections that elicit strong systemic inflammatory responses, which subsequently affect host immune responses. Here we report that memory T cell bystander activation is not limited to induction by systemic inflammation. We initially observe potential T cell bystander activation in a cohort of human vaccine recipients. Using a mouse model system, we then find that memory CD8 + T cells are specifically recruited to sites with activated antigen-presenting cells (APCs) in a CXCR3-dependent manner. In addition, CXCR3 is also necessary for T cell clustering around APCs and T cell bystander activation, which temporospatially overlaps with the subsequent antigen-specific T cell response. Our data thus suggest that bystander activation is part of the initial localized immune response, and is mediated by a site-specific recruitment process of memory T cells. T cell bystander activation is induced by systemic inflammation. Here the authors show, using mouse model systems and correlating with human vaccination data, that localized inflammation elicits bystander activation, and that CXCR3 specifically recruits memory CD8 + T cells to sites of activated antigen-presenting cells for bystander activation.

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch. Chronic itch is a debilitating disorder that can last for months or years. Eczema, or atopic dermatitis, is the most common cause for chronic itch, affecting one in ten people worldwide. Many treatments for the condition are ineffective, and the exact cause of the disease is unknown, but many different types of cells are likely involved. These include skin cells and inflammation-promoting immune cells, as well as nerve cells that detect inflammation, relay itch and pain information to the brain, and regulate the immune system. Learning more about how these cells interact in eczema may help scientists find better treatments for the condition. So far, a lot of research has focused on static ‘snapshots’ of mature eczema lesions from human skin or animal models. These studies have identified abnormalities in genes or cells, but have not revealed how these genes and cells interact over time to cause chronic itch and inflammation. Now, Walsh et al. reveal that immune cells called neutrophils trigger chronic itch in eczema. The experiments involved mice with a condition that mimics eczema, and showed that removing the neutrophils in these mice alleviated their itching. They also showed that dramatic and rapid changes occur in the nervous system of mice suffering from the eczema-like condition. For example, excess nerves grow in the animals’ damaged skin, genes in the nerves that detect sensations become hyperactive, and changes occur in the spinal cord that have been linked to nerve pain. When neutrophils are absent, these changes do not take place. These findings show that neutrophils play a key role in chronic itch and inflammation in eczema. Drugs that target neutrophils, which are already used to treat other diseases, might help with chronic itch, but they would need to be tested before they can be used on people with eczema.

Background CD8 + T cell trafficking to the tumor site is essential for effective colorectal cancer (CRC) immunotherapy. However, the mechanism underlying CD8 + T cell infiltration in colorectal tumor tissues is not fully understood. In the present study, we investigated CD8 + T cell infiltration in CRC tissues and the role of chemokine–chemokine receptor signaling in regulation of T cell recruitment. Methods We screened chemokines and cytokines in healthy donor and CRC tissues from early- and advanced-stage patients using multiplex assays and PCR screening. We also utilized transcription factor activation profiling arrays and established a xenograft mouse model. Results Compared with tumor tissues of early-stage CRC patients, CD8 + T cell density was lower in advanced-stage tumor tissues. PCR screening showed that CXCL10 levels were significantly increased in advanced-stage tumor tissues. CXCR3 (the receptor of CXCL10) expression on CD8 + T cells was lower in the peripheral blood of advanced-stage patients. The migratory ability of CD8 + T cells to CXCL10 depended on CXCR3 expression. Multiplex arrays showed that IL-17A was increased in advanced-stage patient sera, which markedly downregulated CXCR3 expression via activating STAT3 signaling and reduced CD8 + T cell migration. Similar results were found after CD8 + T cells were treated with Th17 cell supernatant. Adding anti-IL-17A or the STAT3 inhibitor, Stattic, rescued these effects in vitro and in vivo. Moreover, survival analysis showed that patients with low CD8 and CXCR3 expression and high IL-17A levels had significantly worse prognosis. Conclusions CD8 + T cell infiltration in advanced-stage tumor was systematically inhibited by Th17 cells via IL-17A/STAT3/CXCR3 axis. Our findings indicate that the T cell infiltration in the tumor microenvironment may be improved by inhibiting STAT3 signaling.

Post-translational modification of chemokines such as CXCL10 can regulate their activity. Albert and colleagues demonstrate that the endogenous peptidase DPP4 cleaves CXCL10 and thereby interferes with T cell recruitment to tumors. The success of antitumor immune responses depends on the infiltration of solid tumors by effector T cells, a process guided by chemokines. Here we show that in vivo post-translational processing of chemokines by dipeptidylpeptidase 4 (DPP4, also known as CD26) limits lymphocyte migration to sites of inflammation and tumors. Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10 and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade. These findings provide direct in vivo evidence for control of lymphocyte trafficking via CXCL10 cleavage and support the use of DPP4 inhibitors for stabilizing biologically active forms of chemokines as a strategy to enhance tumor immunotherapy.

Background Cancers, especially colorectal cancer, are among the most common and deadly diseases in the world, and their incidence is increasing in various countries. Current therapeutic methods, such as chemotherapy, surgery, and immunotherapy, have failed to provide successful treatment without side effects. Therefore, identifying effective therapeutic targets is crucial. Several studies have demonstrated that the expression of the CXCR3 gene, a member of the GPCR family, is elevated in colorectal cancer. Methods In this study, the effect of targeting the CXCR3 gene on the HCT-116 line, a colorectal cancer cell line, was investigated via gene-specific targeting. For this purpose, specific DNAzymes were designed, and the impact of CXCR3 downregulation on cancer cell development was assessed via cell cycle analysis, Annexin V-PI staining, and the wound healing method. Results CXCR3 gene downregulation inhibited the key AKT‒MTOR pathway and reduced proliferation and growth of HCT-116 cells. Moreover, CXCR3 mRNA downregulation increased the apoptosis of these cells. Conclusion Our findings suggest that downregulation of CXCR3 mRNA inhibits colorectal cancer cell growth through inhibition of the AKT‒mTOR pathway. The CXCR3 receptor can be considered a new therapeutic target in colorectal cancer therapy.

CXCR3 is a chemokine receptor that is rapidly induced on naïve T cells following activation, and preferentially remains highly expressed on type‐1 helper (Th1)‐type CD4+ T cells, effector CD8+ T cells and innate‐type lymphocytes, such as natural killer (NK) and NKT cells. CXCR3 is activated by three interferon (IFN)‐γ‐inducible ligands CXCL9 (monokine induced by gamma‐interferon), CXCL10 (interferon‐induced protein‐10) and CXCL11 (interferon‐inducible T‐cell alpha chemoattractant). Although some studies have revealed that these ligands have redundant functions in vivo, other studies have demonstrated that the three CXCR3 ligands can also collaborate and even compete with each other. Differential regulation of the three ligands at specific times in defined anatomically restricted locations in vivo likely participates in the fine control of T‐cell trafficking over the course of an immune response. Among the differences in regulation, CXCL10 is induced by a variety of innate stimuli that induce IFN‐α/β as well as the adaptive immune cell cytokine IFN‐γ, whereas CXCL9 induction is restricted to IFN‐γ. In this review, we will discuss how the balance, timing and pattern of CXCR3 ligand expression appears to regulate the generation of effector T cells in the lymphoid compartment and subsequent migration into peripheral sites of Th1‐type inflammation in which the CXCR3 ligands also then regulate the interactions and migratory behavior of effector T cells in an inflamed peripheral tissue. Our understanding of the significance and complexity of the chemokine superfamily has increased at an explosive pace over the last decade. Although this pace may be slowing down, many questions remain in this field. The February 2011 Special Feature on Chemokines reviews some of these issues: the CXCR3/CXCL9/CXCL10/CXCL11 axis; the role of chemokines in the thymus; and the function of the atypical chemokine receptors DARC and D6.

CXCR3 is a chemokine receptor with three ligands; CXCL9, CXCL10, and CXCL11. CXCL11 binds CXCR3 with a higher affinity than the other ligands leading to receptor internalization. Long ago we reported that one of these chemokines, CXCL10, not only attracts CXCR3+ CD4+ and CD8+ effector T cells to sites of inflammation, but also direct their polarization into highly potent effector T cells. Later we showed that CXCL11 directs the linage development of T-regulatory-1 cells (Tr1). We also observed that CXCL11 and CXCL10 induce different signaling cascades via CXCR3. Collectively this suggests that CXCR3 ligands differentially regulate the biological function of T cells via biased signaling. It is generally accepted that tumor cells evolved to express several chemokine receptors and secrete their ligands. Vast majority of these chemokines support tumor growth by different mechanisms that are discussed. We suggest that CXCL10 and possibly CXCL9 differ from other chemokines by their ability to restrain tumor growth and enhance anti-tumor immunity. Along with this an accumulating number of studies showed in various human cancers a clear association between poor prognosis and low expression of CXCL10 at tumor sites, and vice versa. Finally, we discuss the possibility that CXCL9 and CXCL10 may differ in their biological function via biased signaling and its possible relevance to cancer immunotherapy. The current mini review focuses on exploring the role of CXCR3 ligands in directing the biological properties of CD4+ and CD8+ T cells in the context of cancer and autoimmunity. We believe that the combined role of these chemokines in attracting T cells and also directing their biological properties makes them key drivers of immune function.