RN13

Skip to Main content

CXCL1

Related terms:

Chemokine

Tumor Necrosis Factor Alpha

Ligand

Eicosanoid Receptor on the car it isn't broken

CCL2

Interleukin 17

CXCL2

Monocyte

Protein

Alpha Chemokine

View all Topics

CHEMOKINES, CXC | CXCL1 (GRO1)–CXCL3 (GRO3)

S.W. Chensue, in Encyclopedia of Respiratory Medicine, 2006

CXCL1–3 are members of the CXCL class of chemokines with neutrophil chemotactic and angiogenic biologic properties. These molecules exist as dimers and interact principally with the guanosine nucleotide-protein-coupled, CXCR2 chemokine receptor expressed by neutrophils as well as by other cell types. CXCL1–3 are elicited by microbial products and cytokines and likely contribute to inflammatory and repair responses as part of a broad spectrum of chemotactic mediators. Evidence to date indicates that these molecules participate in multiple pulmonary diseases including infections, adult respiratory distress syndrome, chronic obstructive pulmonary disease, hyperoxia-induced lung injury, fibrosis, and neoplasm.

View chapterPurchase book

CXC Chemokines in Cancer Angiogenesis and Metastases

Ellen C. Keeley, ... Robert M. Strieter, in Advances in Cancer Research, 2010

II Angiogenic CXC Chemokines and Receptors

The angiogenic CXC chemokine family includes CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8 (Table I). In the mouse, all ELR+ CXC chemokines signal via CXCR2, whereas in humans, ELR+ CXC chemokine ligands can signal via both CXCR2 and CXCR1 (Mehrad et al., 2007). CXCR2, however, is considered the major angiogenic receptor in humans since the expression of CXCR2 alone is required for endothelial cell chemotaxis despite the fact that both CXCR1 and CXCR2 are detected on endothelial cells (Addison et al., 2000; Murdoch et al., 1999); and immunoneutralization of CXCR2 blocks the response of human endothelial cells to CXCL8 (Heidemann et al., 2003). Lastly, while only CXCL8 and CXCL6 bind to CXCR1, all the human ELR+ CXC chemokines mediate angiogenesis (Mehrad et al., 2007).

In addition to CXCR2, a unique promiscuous, nonsignaling chemokine receptor, the red blood cell Duffy antigen for chemokines (DARC) binds CXCL1, CXCL5, and CXCL8 and is thought to function as a "decoy" for excess ELR+ CXC angiogenic chemokines, thus creating a less angiogenic environment leading to inhibition of tumor growth and metastasis (Addison et al., 2004). When transfected and overexpressed in a human non-small cell cancer tumor line, and implanted into animals, the DARC-expressing tumors had greater necrosis, decreased blood vessel density, and decreased potential of metastases (Addison et al., 2004); similar findings have been shown using breast cancer cell lines (Wang et al., 2006a). In a transgenic adenocarcinoma mouse model of prostate cancer, DARC-knockout mice developed larger, more aggressive tumors, and the tumors had increased blood vessel density and increased levels of angiogenic ELR+ CXC chemokines compared to wild-type mice (Shen et al., 2006). Moreover, in a separate study, transgenic expression of DARC by mouse endothelial cells resulted in an attenuated angiogenic response to ELR+ CXC chemokines in vivo (Du et al., 2002). From a clinical perspective, since approximately 80% of individuals of African descent lack DARC, it has been suggested that the decreased clearance of angiogenic chemokines may be the mechanism behind their increased mortality from prostate cancer (Shen et al., 2006).

View chapterPurchase book

Cell Recruitment and Angiogenesis

Zoltán Szekanecz, Alisa E. Koch, in Kelley and Firestein's Textbook of Rheumatology (Tenth Edition), 2017

CXC Chemokines in Arthritis

The most relevant CXC chemokines involved in the pathogenesis of arthritis are CXCL1 (groα), CXCL4 (platelet factor 4; PF4), CXCL5 (epithelial cell–derived neutrophil attractant 78; ENA-78), CXCL6 (granulocyte chemotactic protein 2; GCP-2), CXCL7 (connective tissue–activating protein III; CTAP-III), CXCL8 (IL-8), CXCL9 (Mig), CXCL10 (IFN-γ–inducible 10 kDa protein; IP-10), CXCL12 (stromal cell–derived factor 1; SDF-1), CXCL13 (B cell–activating chemokine 1; BCA-1), and CXCL16. All are abundantly expressed in the sera, synovial fluids, and tissues of RA patients.60,67

During the last decade, it has become clear that anti-­citrullinated peptide antibodies (ACPA) are a harbinger of RA.68,69 Given this important finding, we have recently shown that alteration of just one amino acid from arginine to citrulline in CXCL5 (ENA-78) changes its function from a nonmonocyte-recruiting to a monocyte-recruiting chemokine.70

Synovial macrophages are the major source of most CXC chemokines.67,71 CXCL12, 13, and 16 are more peculiar CXC chemokines in many ways. First, although the other CXC chemokines described previously have common receptors, CXCL12, 13, and 16 are specific ligands for CXCR4, 5, and 6, respectively.67,71 CXCL12 promotes angiogenesis despite lacking the glutamyl-leucyl-arginyl (ELR) motif, which is usually required for this function.8,72,73 CXCL12 induces CXCR4-dependent integrin-mediated lymphocyte and monocyte adhesion and migration, as well as osteoclastogenesis, bone resorption, and thus radiographic progression in RA.74-80 CXCL13 is also expressed by synovial fibroblasts, T cells, and ECs in RA.81,82 CXCL16 is secreted by synovial macrophages and fibroblasts and is involved in mononuclear cell recruitment into the RA synovium.83-86

View chapterPurchase book

The Role of Myeloid-Derived Suppressor Cells in Immunosuppression in Brain Tumors

K. Gabrusiewicz, ... A.B. Heimberger, in Translational Immunotherapy of Brain Tumors, 2017

Chemokine and Cytokine Approaches

MDSCs are specifically recruited to the hypoxic TME via chemotactic factors such as CXCL1, CXCL12, CXCL5, CCL2, CXCL2, and S100A8/A9. In syngeneic and xenograft murine glioma model systems, administration of an anti-CCL2 antibody can decrease the number of MDSCs and TAMs in the TME, leading to prolonged survival of tumor-bearing mice80 (Table 4.2). Of note, chemokines can be redundant, and therefore upregulation of alternative chemokine pathways is conceivable in the setting of focal targeting. However, upregulation of several of these chemokines is specifically mediated by STAT3,33 rendering it a viable therapeutic target. Cancer cells also secrete factors like prostaglandin E2 (PGE2) and CXCL12 (also known as stromal cell-derived factor 1) that participate in the recruitment of MDSCs to the tumor site, separate from hypoxia-induced mechanisms.32 Cyclooxygenase-2 (COX-2) inhibitors such as acetylsalicylic acid or celecoxib can prevent production of PGE2, reduce CCL2-mediated accumulation of CD11b+Ly6G+ granulocytic MDSCs in both bone marrow and the TME, and increase CD8+ T cells in a CXCL10-dependent manner.70 These mechanisms are by no means specific to the MDSC population and have not shown significant clinical activity.81–83 Silencing glioma-derived galectin-1 significantly prolonged the survival of glioma-bearing mice by decreasing the accumulation of glioma-infiltrating microglia/macrophages and MDSCs,84 but currently there is no viable therapeutic approach for accomplishing this in human subjects.

Table 4.2. MDSCs as a Target for Glioblastoma Therapy

DrugsMechanism of ActionPreclinical and Clinical OutcomeAnti-CCL2Decreases chemotaxis of MDSCs and TAMsActivity in GL261 glioma model

No clinical trialCOX-2 inhibitors (acetylsalicylic acid, celecoxib)Prevents production of PGE2, decreases CCL2-dependent chemotaxis of MDSCs, increases infiltration CD8+ T cells by enhancing expression of CXCL10Activity in murine glioma model

No significant clinical activityGalectin-1 knock downDecreases accumulation of MDSCs and TAMsActivity in GL261 glioma model

No clinical therapeutic approach available13-Cis-retinoic acidInduces differentiation of MDSCsNot tested in glioma model

No clinical benefitsIL-4Rα aptamerInduces apoptosis of MDSCs by STAT6 suppressionNot tested in glioma model

No clinical trialArg1 inhibitor (nor-NOHA)Prevents l-arginine depletion in TME, restores T cell functionNot tested in glioma model

No clinical triall-arginine supplementationCompensates l-arginine depletion in TME, restores T cell functionNot tested in glioma model phase I study with oral l-arginine (NCT02017249)CD200R antagonist peptide (A26059)Blocks expansion of MDSCs, reduces Arg1 secretion, activates CD8+ T cell responseActivity in GL261 glioma model

No clinical trialAnti-FGL2 antibodyReduces MDSC number, TAMs, CD39+ Tregs, and PD-1Activity in GL261 glioma model

No clinical trialAnti–TGF-β antibodyEnhances iNOS production while decreasing Arg1 expression in MDSCsNo activity in GL261 glioma model or U87MG xenograft model

No significant clinical benefitsIL-12 immunotherapyDecreases MDSC number, increases expression of CD80 and MHC II on MDSCsActivity in GL261 model phase I study with adenovirus expressing IL-12 (NCT02026271)miR-142-3pBlocks TGFBR1 signaling and induces apoptosis in M2- polarized macrophagesActivity in GEMM of glioma and GL261 glioma model

No clinical trialAnti-VEGF and anti–G-CSF antibodiesSuppresses MDSCs, Bv8, and tumor vasculatureNot tested in glioma model

No clinical trialSunitinibDecreases MDSC number, induces T cell functionActivity in GEMM of glioma, no activity in U87MG xenograft model

No clinical benefitsWP1066Blocks STAT3 pathway and M2 polarizationActivity in GEMM of glioma and GL261 glioma model phase I study with WP1066 (NCT01904123)CSF-1R inhibitors (BLZ945, PLX3397)Blocks M2-polarized macrophagesActivity in GEMM of glioma and GL261 glioma model

No clinical trial

Arg1, arginase 1; Bv8, Bombina variegata peptide 8; COX-2, cyclooxygenase 2; CSF-1R, colony-stimulating factor 1 receptor; FGL2, fibrinogen-like protein 2; G-CSF, granulocyte colony-stimulating factor; GEMM, genetically engineered mouse model; IL, interleukin; iNOS, inducible nitric oxide synthase; MDSC, myeloid-derived suppressor cell; MHC II, major histocompatibility complex class II; PD-1, programmed cell death protein 1; PGE2, prostaglandin E2; STAT, signal transducer and activator of transcription; TAM, tumor-associated macrophage; T cell, T lymphocyte; TGF-β, transforming growth factor beta; TGFBR1, transforming growth factor beta receptor 1; TME, tumor microenvironment; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.

View chapterPurchase book

Immunotherapy of Cancer

Eduardo Bonavita, ... Alberto Mantovani, in Advances in Cancer Research, 2015

5.1 Neutrophil Recruitment and Their Prognostic Significance in Tumors

Within the tumor microenvironment, a number of CXC chemokines (e.g., CXCL1, CXCL2, CXCL3, CXCL5, CXCL8), known for their neutrophil chemoattractant properties, are produced by tumor and stromal cells and have been related to cancer initiation, to the promotion of tumor angiogenesis, and metastasis (Keeley et al., 2010; Lazennec & Richmond, 2010; Mantovani et al., 2011). For example, evidence derived from murine models described an important role for the CXCR2 signaling pathway in lung and pancreatic cancer promotion (Ijichi et al., 2011; Keane, Belperio, Xue, Burdick, & Strieter, 2004). In various murine models of cancers (inflammation-associated skin cancer, colitis-associated or spontaneous intestinal cancer), CXCR2 abrogation or neutrophil depletion inhibited both inflammation-induced and spontaneous carcinogenesis (Jamieson et al., 2012). Moreover, in a murine model of graft tumor, CXCL17 promoted the recruitment of myeloid CD11b+Gr1+F4/80− cells within the tumor, favoring tumor growth, angiogenesis, and metastatic behavior (Matsui et al., 2012). In humans, HCC cells and head and neck squamous cell carcinoma (HNSCC) cell lines recruited neutrophils in a CXCR2-dependent manner through the production of CXCL8 (Kuang et al., 2011) and macrophage-inhibiting factor (MIF; Dumitru et al., 2011; Trellakis, Farjah, et al., 2011). Moreover, in a wide cohort of HCC tumors, correlations between increased CXCL5 expression, neutrophil infiltration, and poor patients' survival were found (Zhou et al., 2012). In addition, in a murine model of lung cancer determined by K-ras activation and p53 abrogation, TAM and TAN precursors relocated from the spleen to the tumor and splenectomy significantly reduced the infiltration of myeloid cells within the tumor (Cortez-Retamozo et al., 2012). In addition, Angiotensin II was identified as a pivotal factor in the amplification of hematopoietic self-renewal (Cortez-Retamozo et al., 2013).

Various epidemiological evidences described a negative correlation between TANs and patient clinical outcome in metastatic and localized renal cell carcinoma, bronchioloalveolar carcinoma, HCC, colorectal cancer, and head and neck cancer (Donskov, 2013; Jensen et al., 2009; Kuang et al., 2011; Rao et al., 2012; Trellakis, Bruderek, et al., 2011; Wislez et al., 2003). Moreover, higher tumor-infiltrating neutrophil density was associated with higher histological grade in glioma (Fossati et al., 1999) and more aggressive pancreatic cancer (Reid et al., 2011). In contrast, the association between neutrophil infiltration and patients' clinical outcome remains controversial for some tumor types, such as gastric and colorectal cancer (Caruso et al., 2002; Hirt et al., 2013). These controversial evidences may be due to variability in the methods used to identify neutrophils within tumors (e.g., immunohistochemistry, hematoxylin–eosin staining), as well as the choice of patient datasets and outcomes.

View chapterPurchase book

Chemokine Receptors

T. Sobolik-Delmaire, ... A. Richmond, in Encyclopedia of Biological Chemistry (Second Edition), 2013

Tumor Growth and Metastasis

Many cancer cells such as melanomas express a number of chemokines, including CXCL8, CXCL1-3, CCL5, and CCL2, which have been implicated in tumor growth and progression. Recent studies have demonstrated organ-specific patterns of melanoma metastasis that correlate with their expression of specific chemokine receptors, including CXCR4, CCR7, CCR9, and CCR10. The chemokine receptors CXCR4 and CXCR7 are also found on breast cancer cells and their ligands are highly expressed at sites associated with breast cancer metastases. Other models in which CXCR4 has been suggested to play a role in metastasis are ovarian, prostate, and lung cancers. In addition, studies have shown that decreased expression of Duffy and D6 decoy receptors in breast cancer inversely correlate with lymph node metastases and increased survival rates. Increased levels of CCL2 expression in breast cancer have been associated with increased levels of tumor-associated macrophages, correlating with invasive phenotype and poor prognosis. It is postulated that chemokine receptors and their ligand pairs play a role in the migration of tumor cells from their primary site via the circulation to the preferential sites of metastases.

View chapterPurchase book

Do Chemokines Have a Role in the Pathophysiology of Depression?

Gaurav Singhal, Bernhard T. Baune, in Inflammation and Immunity in Depression, 2018

CXC Chemokines in CNS

Unlike CC chemokines that primarily attract monocytes and T lymphocytes, CXC chemokines, particularly CXCL1–CXCL8, ligands for CXCR2, have been shown to primarily attract neutrophils to regulate CNS inflammatory states (Murphy et al., 2000). However, whether neutrophil chemotaxis by CXC chemokines aids or deters neuronal survival and repairs under inflammatory conditions remains unclear (Jaerve & Müller, 2012; Stirling, Liu, Kubes, & Yong, 2009). For example, both neuroprotective and neurodegenerative effects of CXCR2 and its ligand CXCL1 have been reported in the mouse model of EAE (Kerstetter, Padovani-Claudio, Bai, & Miller, 2009; Omari, Lutz, Santambrogio, Lira, & Raine, 2009). Similarly, CXCL8 produced in the injured brain is essential for the migration and activation of leukocytes, in particular polymorphonuclear neutrophils toward the lesioned brain region (Dirnagl, Iadecola, & Moskowitz, 1999). Activated neutrophils, in turn, produce a variety of toxic mediators, such as cytokines, reactive oxygen and nitrogen species, and lipid mediators that may lead to transient brain ischemia and other neuroinflammatory disorders (Garau et al., 2005; Villa et al., 2007; Witko-Sarsat, Rieu, Descamps-Latscha, Lesavre, & Halbwachs-Mecarelli, 2000). However, CXCL8 has also been shown to be neuroprotective in a model of β-amyloid toxicity in vitro (Watson & Fan, 2005).

CXCL9–CXCL11 chemokines are evidently detrimental and exert pro-inflammatory effects through CXCR3-mediated chemotaxis of NK cells, Th1 cells, and associated classically activated (M1) pro-inflammatory monocyte-derived macrophages (Murphy et al., 2000). For example, CXCL10 that can cross the vascular endothelial cells from the CNS (Mordelet, Davies, Hillyer, Romero, & Male, 2007) shows reduction in migration when its CXCR3 receptor is blocked. This, in turn, has shown to reduce tissue damage and functional deficit in the mouse and rat models of EAE (Jenh et al., 2012).

CXCL12 has received a great deal of attention recently and found to be present in neurons with its receptors CXCR4 and CXCR7 expressed in diverse brain regions (Guyon, 2014). Its presence has also been reported in glial cells in the hippocampus, cerebral cortex substantia nigra, striatum, hypothalamus, and globus pallidus (Heinisch & Kirby, 2010). It has been shown to crosstalk with neurotransmitter systems, in particular with GABAergic systems, glutamatergic systems, and serotonergic systems (Guyon, 2014; Heinisch & Kirby, 2010), and is important for neurogenesis and neuronal migration during development (Heinisch & Kirby, 2010). Likewise, CXCL13 with its receptor CXCR5 modulates the maturation and proliferation of subgranular cells in the hippocampal dentate gyrus (Stuart, Corrigan, & Baune, 2014) (Table 3).

Table 3. Biological Characteristics of CXC Chemokines in CNS Functions

CXC

Chemokines and SynonymsReceptor(s)CNS FunctionsClassical Peripheral FunctionsReferencesCXCL1 (Gro-α, GRO1, NAP-3, KC)CXCR2NSC/NPC chemotaxis and differentiationnø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015; Tran, Ren, Veldhouse, & Miller, 2004)CXCL2 (Gro-β, GRO2, MIP-2α)CXCR2Unknownnø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015; Wolpe et al., 1989)CXCL3 (GRO3, MIP-2β)CXCR2Unknownmø, nø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL4 (platelet factor-4)CXCR3BUnknownmø, nø, fibroblasts chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL5 (ENA-78)CXCR2Unknownnø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL6 (GCP-2)CXCR1, CXCR2Unknownnø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL7 (NAP-2, CTAPIII, β-Ta, PEP)CXCR2Unknownnø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL8 (IL-8, NAP-1, MDNCF, GCP-1)CXCR1, CXCR2NSC/NPC chemotaxis, HPA axis modulationnø, eø, bø, T Lø, B Lø, NK, DC chemotaxis, nø, mø, bø activation(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL9 (MIG, CRG-10)CXCR3NSC/NPC differentiation, PIC infiltrationT Lø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Murphy et al., 2000; Ono et al., 2003; Stuart et al., 2015)CXCL10 (IP-10, CRG-2)CXCR3PIC infiltrationmø, T Lø, NK, DC chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Murphy et al., 2000; Ono et al., 2003; Stuart et al., 2015)CXCL11 (IP-9, I-TAC, β-R1)CXCR3, CXCR7PIC infiltrationT Lø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Murphy et al., 2000; Ono et al., 2003; Stuart et al., 2015)CXCL12 (SDF-1, PBSF)CXCR4, CXCR7NSC/NPC chemotaxis, enhances neurogenesis, modulates glutamate and GABA neurotransmission, HPA axis modulationT Lø, mø chemotaxis, inhibits hematopoietic stem cell proliferation and differentiation, promotes angiogenesis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL13 (BCA-1, BLC)UnknownB Lø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL14 (BRAK, bolekine)Unknownmø, NK, DC chemotaxis and activation, inhibits angiogenesis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL15 (lungkine, WECHE)Unknownnø chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL16 (SRPSOX)CXCR6UnknownT Lø, NK chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)CXCL17 (DMC, VCC-1)Unknownmø, DC chemotaxis(Le et al., 2004; Murdoch & Finn, 2000; Ono et al., 2003; Stuart et al., 2015)

mø, monocyte/macrophage; Lø, lymphocyte; nø, neutrophil; bø, basophil; eø, eosinophil; DC, dendritic cell; NK, natural killer cell; NSC/NPC, neural stem/progenitor cell; PIC, peripheral immune cell; HPA axis, hypothalamus-pituitary–adrenal axis.

View chapterPurchase book

Chemokines

Sunny C. Yung, Joshua M. Farber, in Handbook of Biologically Active Peptides (Second Edition), 2013

Neutrophil Activation and Trafficking

The ELR+ CXC chemokines attract and activate neutrophils. There are seven members in this family (CXCL1, 2, 3, 5, 6, 7, and 8). Separate chemokine domains were found to be critical for different aspects of neutrophil activation. Such observations probably stem from roles for these domains in the activation of different chemokine receptors. For example, CXCL8, in contrast to other ELR+ CXC chemokines, can bind and activate both CXCR1 and CXCR2 (although affinities for the two receptors differ). Mutational analysis of CXCL8 shows that the ELR domain is critical for neutrophil degranulation (an effect mediated by CXCR1) but not neutrophil chemotaxis (an effect mediated by CXCR2). The C-terminal domain probably also participates in receptor binding, because C-terminal truncation of CXCL8 decreases receptor affinity. Interestingly, a sequence that includes the GP dipeptide and is found just N-terminal to the third conserved cysteine in most ELR+ positive chemokines is active as a chemoattractant and resembles a proteolytic fragment of collagen, PGP, that is able to recruit neutrophils via both CXCR1 and CXCR2.28

View chapterPurchase book

Molecular and Cellular Basis of Metastasis: Road to Therapy

M. Yao, ... N. Cheng, in Advances in Cancer Research, 2016

3.4 CXCL8

As an ELR + chemokine, CXCL8 (also known as IL-8) shares many functions with CXCL1 in inflammation and cancer. While polymorphisms of CXCL8 or CXCR1, a binding receptor shows variable associations with prognosis (Tables 6 and 7), increased RNA, and protein expression of CXCL8 or CXCR1 frequently correlates with unfavorable cancer prognosis (Tables 9 and 10). CXCL8 stimulates promotes angiogenesis in corneal models (Koch et al., 1992), and tumor angiogenesis in animal models of: pancreatic, glioblastoma, lung carcinoma, prostate, ovarian, and colon cancer (Arenberg et al., 1996; Brat, Bellail, & Van Meir, 2005; Devapatla, Sharma, & Woo, 2015; Inoue et al., 2000; Matsuo, Ochi, et al., 2009; Ning et al., 2011). CXCL8 also stimulates chemotaxis of neutrophils and basophils (Geiser et al., 1993). Similarly to CXCL1, CXCL8 overexpression in cancer cell lines enhances tumor cell growth and invasion in in vitro and in vivo in melanoma models (Schadendorf et al., 1993; Singh, Gutman, Reich, & Bar-Eli, 1995). Yet, there are also key differences between CXCL1 and CXCL8. In contrast to CXCL1 and CXCR2, CXCL8, and CXCLR1 are expressed in humans, but not in mice (Mestas & Hughes, 2004; Zlotnik & Yoshie, 2000). CXCL8 binds preferentially to CXCR1 than CXCR2 (Nasser et al., 2009). Pharmacologic blockade of CXCR1 or CXCL8 selective antagonists inhibit CXCL8-mediated tumor growth and invasion as demonstrated in breast and lung cancer models (Ginestier et al., 2010; Khan, Wang, et al., 2015). Emerging studies have also revealed unique functions and mechanisms for CXCL8 signaling in cancer progression.

CXCL8 plays an important role in cancer stem cell renewal and survival. In breast cancer, CXCL8 enhances self-renewal of ALDH1 + cells and promotes cancer cell survival of breast cancer cell through CXCR1-dependent mechanisms (Charafe-Jauffret et al., 2009). Treatment of breast cancer cells with CXCR1 neutralizing antibodies or the small molecule inhibitor repertaxin decrease Aldeflour activity and enhance cellular apoptosis, which are mediated through FasL, AKT, FAK, and Fox03A signaling mechanisms (Ginestier et al., 2010). In pancreatic cancer, CXCL8 stimulates sphere formation and self-renewal of CD44 +/CD24– cells, which are inhibited by pharmacologic or antibody neutralization of CXCR1 (Chen et al., 2014; Maxwell, Neisen, Messenger, & Waugh, 2014). In nasopharyngeal carcinoma, CXCL8 stimulated growth of tumor spheroids in vitro through a PI-3K/AKT- and CXCR2-dependent mechanism (Lo et al., 2013). CXCL8 promotes survival of prostate cancer cells to 5-FU through CXCR2- and Bcl2-dependent mechanisms (Wilson et al., 2012). These studies indicate that CXCL8 regulates cancer progression by signaling to cancer cells to mediate stem cell renewal and survival, with important implications on chemoresistance.

View chapterPurchase book

Regulated Necrosis and Its Immunogenicity

Wulf Tonnus, Andreas Linkermann, in Clinical Immunology (Fifth Edition), 2019

Necroptosis

Necroptosis is the best characterized mode of RN. It was discovered as a type of necrotic cell death in apoptosis-resistant cell lines. Classically, it is induced upon tumor necrosis factor-α (TNF-α) stimulation whilst apoptosis is blocked (e.g., by a pan-caspase inhibitor, such as zVAD). In this context, TNFR1, Fas, and other death receptors (described at pathways of extrinsic apoptosis, see above) transduce this signal into the cell (Fig. 13.6).

RIPK1, a key checkpoint of cellular fate, contains a unique motif next to its DD referred to as RIP homotypic interacting motif (RHIM). This motif is contained in only four proteins within the whole mammalian proteome, and all these proteins are associated with the regulation of necroptosis. The necrosome, a higher order structure with a poly-RIPK3 backbone, is central to necroptosis execution and can, next to named death receptor–associated pathway, also be engaged by TRIF-binding TLR3 and TLR4, as well as by viral sensing protein DNA-dependent activator of interferon regulatory factors (DAIs).12 Recently, DAI (also known as ZBP1) has been demonstrated to mediate in utero lethality of RIPK1-deficient mice by forcing RIPK3 oligomerization, which places inactive RIPK1 as an inhibitor of necroptosis. The RIPK1 kinase inhibitor necrostatin-1 (Nec-1) seems to stabilize this conformation and thereby inhibit necroptosis on death receptor activation by not releasing RIPK1s' inhibition to RIPK3 oligomerization.

Downstream of the active necrosome, mixed lineage kinase-like domain protein (MLKL) becomes phosphorylated by RIPK3 (see Fig. 13.5). After phosphorylation of MLKL, this pseudokinase forms oligomers targeting the plasma membrane via its four-helical bundle (4HB) motif to mediate plasma membrane rupture and necrotic cell death by currently undefined means. Phosphorylated MLKL (pMLKL) is required, but is not sufficient to execute necroptosis. Whether pMLKL directly forms pores or mediates pore formation is unknown (as well as for gasdermins in pyroptosis). However, this is of great interest as pMLKL targets multiple intracellular membranes, translocates to the nucleus to induce CXCL1/IL-33, and is stably expressed in terminally differentiated cells, such as podocytes and endothelia, without killing these. Taken together, this might point to a still-unknown physiological role of pMLKL.

Mice deficient in RIPK3 or FADD and MLKL die following challenge with influenza A virus, which has been demonstrated to depend on DAIs' RHIM domain. Viruses also indirectly activate necroptosis by JAK-STAT–dependent protein kinase R upregulation.

Bacterial infection is sensed via TLR3 and TLR4. This also recruits RHIM domain–containing protein TRIF, which leads to necrosome formation. Current understanding favors the idea that necroptosis is an evolutionary conserved program to defend against viruses and certain bacteria. In line with this, some viruses express caspase-inhibitors, such as crmA (e.g., cowpox virus), whereas viral protein M45 (e.g., CMV) specifically targets necroptosis. M45 has been demonstrated to be a viral RHIM domain and thus suppresses DAI-induced RIPK3 oligomerization within the necrosome. Interestingly, cytomegalovirus (CMV) is a member of the herpesvirus family, which is famous for its persistence within the host. One might conclude that this virus adapted to the necroptotic trapdoor by this mechanism.

During necroptosis, some chemokines (Chapter 10) and cytokines (Chapter 9) are actively produced to be released apart from DAMPs. These include CXCL1 and IL-33, a stimulator of ST2 signaling on Tregs. This suggests that necroptosis, apart from being immunogenic through the release of DAMPs, also limits the inflammatory response to a certain surrounding of the damage by creating a microenvironment that may prevent necroptosis from causing a systemic inflammatory response syndrome (SIRS) and death. Necroptosis may thus be the least immunogenic RN pathway (see Fig. 13.4).

Clinical Relevance

Selection of Clinically Relevant Conditions Associated With Necroptosis

•

Acute liver failure

•

Autoimmune disorders

•

Acute respiratory distress syndrome (ARDS)

•

Cancer (necrosis in the center of solid tumors)

•

Chemotherapy

•

Contrast-induced acute kidney injury (CIAKI)

•

Myocardial infarction

•

Sepsis

•

Solid-organ transplantation

•

Stroke

•

Transplant rejection

Necroptosis critically contributes to diverse pathophysiological settings, such as ischemia–reperfusion injury in solid organ transplantations, myocardial infarction, stroke, and SIRS. RIPK3- and MLKL-deficient mice have been demonstrated to be protected from preclinical models of such diseases by several independent groups, so inhibitors of necroptosis (RIPK1 kinase inhibitors, RIPK3 kinase inhibitors, and MLKL inhibitors) have entered phase I and phase II clinical trials. No cell death–preventing therapy has been approved by the US Food and Drug Administration (FDA) as of the writing of this chapter. However, preclinical and first clinical data are very promising. Necroptosis inhibitors may soon become the first-in-class compounds to prevent RN.13

Skip to main contentSkip to article



Access through your institution

Get Access

Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section

Volume 96, Issue 2, March 1995, Pages 114-120

Main article

Two distinct cervical N13 potentials are evoked by ulnar nerve stimulation

Author links open overlay panelGiampietroZanetteAlbertoPolo

Show more

Outline

Share

Cite

https://doi.org/10.1016/0168-5597(94)00212-WGet rights and content

Abstract

To investigate the dual nature of the posterior neck N13 potential, we attempted to establish the presence of a latency dissociation between caudal (cN13) and rostral (rN13) potentials on stimulating the ulnar nerve, in view of its lower radicular entry compared to the median nerve. SEPs were evaluated in 24 normal subjects after both median and ulnar nerve stimulation. cN13 was prominent in the lower cervical segments, and rN13 was localized mainly in the upper ones using anteroposterior and longitudinal bipolar montage, respectively. The N9-cN13 interpeak latency did not differ significantly from N9-rN13 when stimulating the median nerve. On the other hand, the N9-rN13 interpeak was significantly longer than the N9-cN13 interpeak when the ulnar nerve was stimulated. The rN13 presented the same latency as P13-P14 far-field potentials in 17 out of 24 ulnar nerves tested. Therefore, the ulnar nerve stimulation evokes two distinct posterior neck N13 potentials. It is widely accepted that the caudal N13 is a postsynaptic potential reflecting the activity of the dorsal horn interneurons in the lower cervical cord. We suggest that the rostral N13 is probably generated close to the cuneate nucleus, which partly contributes to the genesis of P13-P14 far-field potentials.

Previous

Next 

Somatosensory evoked potentials

Median nerve

Upper limbs

N13

Scalp P13-P14

Recommended articlesCiting articles (20)

Cell

Volume 141, Issue 4, 14 May 2010, Pages 692-703

Article

The Vomeronasal Organ Mediates Interspecies Defensive Behaviors through Detection of Protein Pheromone Homologs

Author links open overlay panelFabioPapes123LisaStowers1

Show more

Outline

Share

Cite

https://doi.org/10.1016/j.cell.2010.03.037Get rights and content

Under an Elsevier user license

open archive

Referred to by

Ivan Rodriguez

The Chemical MUPpeteer

Cell, Volume 141, Issue 4, 14 May 2010, Pages 568-570

Download PDF

Summary

Potential predators emit uncharacterized chemosignals that warn receiving species of danger. Neurons that sense these stimuli remain unknown. Here we show that detection and processing of fear-evoking odors emitted from cat, rat, and snake require the function of sensory neurons in the vomeronasal organ. To investigate the molecular nature of the sensory cues emitted by predators, we isolated the salient ligands from two species using a combination of innate behavioral assays in naive receiving animals, calcium imaging, and c-Fos induction. Surprisingly, the defensive behavior-promoting activity released by other animals is encoded by species-specific ligands belonging to the major urinary protein (Mup) family, homologs of aggression-promoting mouse pheromones. We show that recombinant Mup proteins are sufficient to activate sensory neurons and initiate defensive behavior similarly to native odors. This co-option of existing sensory mechanisms provides a molecular solution to the difficult problem of evolving a variety of species-specific molecular detectors.