DOCSLIB.ORG

Chemokine CCL5 Promotes Robust Optic Nerve Regeneration and Mediates Many of the Effects of CNTF Gene Therapy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chemokine CCL5 Promotes Robust Optic Nerve Regeneration and Mediates Many of the Effects of CNTF Gene Therapy Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy Lili Xiea,b,c, Yuqin Yina,b,c, and Larry Benowitza,b,c,d,e,1 aLaboratories for Neuroscience Research in Neurosurgery, Department of Neurosurgery, Boston Children’s Hospital, Boston, MA 02115; bF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115; cDepartment of Neurosurgery, Harvard Medical School, Boston, MA 02115; dDepartment of Ophthalmology, Harvard Medical School, Boston, MA 02115; and eProgram in Neuroscience, Harvard Medical School, Boston, MA 02115 Edited by Keith R. Martin, University of Cambridge, Cambridge, United Kingdom, and accepted by Editorial Board Member Jeremy Nathans January 25, 2021 (received for review August 17, 2020) Ciliary neurotrophic factor (CNTF) is a leading therapeutic candidate (rCNTF) can promote optic nerve regeneration (20, 30, 31), for several ocular diseases and induces optic nerve regeneration in others find little or no effect unless SOCS3 (suppressor of cytokine animal models. Paradoxically, however, although CNTF gene ther- signaling-3), an inhibitor of the Jak-STAT pathway, is deleted in apy promotes extensive regeneration, recombinant CNTF (rCNTF) RGCs (5, 6, 32). In contrast, multiple studies show that adeno- has little effect. Because intraocular viral vectors induce inflamma- associated virus (AAV)-mediated expression of CNTF in RGCs tion, and because CNTF is an immune modulator, we investigated induces strong regeneration (33–40). The basis for the discrepant whether CNTF gene therapy acts indirectly through other immune effects of rCNTF and CNTF gene therapy is unknown but is of mediators. The beneficial effects of CNTF gene therapy remained considerable interest in view of the many promising clinical and unchanged after deleting CNTF receptor alpha (CNTFRα)inretinal preclinical outcomes obtained with CNTF to date. ganglion cells (RGCs), the projection neurons of the retina, but were Because intravitreal virus injections induce inflammation (41), diminished by depleting neutrophils or by genetically suppressing we investigated the possibility that CNTF, a known immune monocyte infiltration. CNTF gene therapy increased expression of modulator (42–44), might act by elevating expression of other C-C motif chemokine ligand 5 (CCL5) in immune cells and retinal glia, immune-derived factors. We report here that the beneficial effects NEUROSCIENCE and recombinant CCL5 induced extensive axon regeneration. Con- of CNTF gene therapy in fact require immune system activation versely, CRISPR-mediated knockdown of the cognate receptor (CCR5) and elevation of C-C motif chemokine ligand 5 (CCL5). Depletion in RGCs or treating wild-type mice with a CCR5 antagonist repressed of neutrophils, global knockout (KO) or RGC-selective deletion the effects of CNTF gene therapy. Thus, CCL5 is a previously unrec- of the CCL5 receptor CCR5, or a CCR5 antagonist all suppress ognized, potent activator of optic nerve regeneration and mediates many of the effects of CNTF gene therapy. the effects of CNTF gene therapy, whereas recombinant CCL5 (rCCL5) promotes axon regeneration and increases RGC survival. ciliary neurotrophic factor | retinal ganglion cells | regeneration | These studies point to CCL5 as a potent monotherapy for optic neuroinflammation nerve regeneration and to the possibility that other applications of CNTF and other forms of gene therapy might similarly act indi- rectly through other factors. ike most pathways in the mature central nervous system (CNS), Lthe optic nerve cannot regenerate once damaged due in part to cell-extrinsic suppressors of axon growth (1, 2) and the low intrinsic Significance growth capacity of adult retinal ganglion cells (RGCs), the projec- tion neurons of the eye (3–5). Consequently, traumatic or ischemic CNTF is a leading therapeutic candidate for glaucoma and other optic nerve injury or degenerative diseases such as glaucoma lead to ocular diseases and is widely used experimentally to promote irreversible visual losses. Experimentally, some degree of regener- axon regeneration after optic nerve injury. Paradoxically, whereas ation can be induced by intraocular inflammation or growth factors CNTF gene therapy is neuroprotective for retinal ganglion cells expressed by inflammatory cells (6–10), altering the cell-intrinsic and promotes considerable regeneration following optic nerve growth potential of RGCs (3–5), enhancing physiological activity injury, recombinant CNTF has little effect. We show that CNTF (11, 12), chelating free zinc (13, 14), and other manipulations gene therapy exacerbates the inflammatory reaction to virally (15–19). However, the extent of regeneration achieved to date re- mediated gene therapy, leading to widespread expression of mains modest, underlining the need for more effective therapies. chemokine CCL5. Blocking CCL5 signaling abrogates most neuro- Ciliary neurotrophic factor (CNTF) is a leading therapeutic protective and axon-promoting effects of CNTF gene therapy, candidate for glaucoma and other ocular diseases (20–23). Acti- whereas recombinant CCL5 largely mimics the beneficial effects of vation of the downstream signal transduction cascade requires CNTF gene therapy. Thus, this study identifies a potent, previously CNTF to bind to CNTF receptor-α (CNTFRα) (24), which leads unknown agent for optic nerve regeneration and raises general questions about interpreting results of gene therapy studies. to recruitment of glycoprotein 130 (gp130) and leukemia inhibi- tory factor receptor-β (LIFRβ) to form a tripartite receptor α Author contributions: L.X., Y.Y., and L.B. designed research; L.X. performed research; L.X. complex (25). CNTFR anchors to the plasma membrane through and Y.Y. analyzed data; and L.X. and L.B. wrote the paper. a glycosylphosphatidylinositol linkage (26) and can be released The authors declare no competing interest. and become soluble through phospholipase C-mediated cleavage This article is a PNAS Direct Submission. K.R.M. is a guest editor invited by the (27). CNTF has been reported to activate STAT3 phosphorylation Editorial Board. in retinal neurons, including RGCs, and to promote survival, but it Published under the PNAS license. is unknown whether these effects are mediated by direct action of 1To whom correspondence may be addressed. Email: larry.benowitz@childrens. CNTF on RGCs via CNTFRα (28). Our previous studies showed harvard.edu. that CNTF promotes axon outgrowth from neonate RGCs in This article contains supporting information online at https://www.pnas.org/lookup/suppl/ culture (29) but fails to do so in cultured mature RGCs (8) or doi:10.1073/pnas.2017282118/-/DCSupplemental. in vivo (6). Although some studies report that recombinant CNTF Published February 24, 2021. PNAS 2021 Vol. 118 No. 9 e2017282118 https://doi.org/10.1073/pnas.2017282118 | 1of11 Downloaded by guest on September 23, 2021 Results with GFAP vs. CNTFRα with TUJ1; Fig. 2C). Thus, in the retina, CNTF Gene Therapy Induces Optic Nerve Regeneration. Our initial as elsewhere in the mature CNS, CNTFRα is expressed primarily study tested whether virally mediated CNTF delivery does in fact in nonneuronal cells (46). This localization pattern does not appear produce a qualitatively different outcome from high doses of tobealteredbyCNTFgenetherapy(Fig.2A). Despite the absence rCNTF protein. We tested a range of rCNTF concentrations cor- of protein staining in RGCs, in situ hybridization (RNA Scope) responding to those reported to be effective (5, 30), adjusting for detects measurable CNTFRa mRNA in these cells (Fig. 2 B, Top). differences in volume between the rat and mouse eyes as needed. The accuracy of this signal was verified using an AAV2 expressing Compared to bovine serum albumin (BSA)-injected controls, a small hairpin RNA (shRNA) to knock down CNTFRα expres- rCNTF at concentrations of 0.03, 0.1, 0.3, and 0.5 μg/μLdidnot sion in RGCs (AAV2-anti-CNTFRa shRNA). Two weeks after improve regeneration (Fig. 1 A and C) nor RGC survival (Fig. 1 B AAV2-sh-CNTFR injection, in situ hybridization revealed a near- and D). To more closely approximate the continuous delivery of complete loss of CNTFRα mRNA in RGCs (P < 0.001; Fig. 2B). CNTF by gene therapy, we also tested three injections of rCNTF CNTFRα knockdown did not diminish the effects of CNTF gene (2 d before, the day of, and 3 d after optic nerve injury), which again therapy on either axon regeneration (P = 0.344; Fig. 2B)orRGC yielded little optic nerve regeneration (SI Appendix,Fig.S1A–D). survival (P = 0.538; Fig. 2 E–H). Thus, the effects of CNTF gene CNTF gene therapy was carried out using an AAV that targets therapy do not appear to require the expression of CNTFRα in RGCs (and some amacrine cells). AAV2-CNTF increased CNTF RGCs. Although it remains possible that RGCs might import bi- mRNA levels ∼30-fold above background and ∼20-fold above the ologically relevant levels of CNTFRα from another source, the control virus 2 wk after transfection (P < 0.05: AAV2-CNTF vs. near absence of CNTFRα protein detected in RGCs and results AAV2-GFP; n = 4 retinas per group; SI Appendix,Fig.S1E). CNTF reported below (in TheEffectsofCNTFGeneTherapyAre gene therapy led to both robust axon regeneration and improved Mediated Primarily via Chemokine CCL5) argue against this RGC survival (P < 0.001 and P < 0.01, respectively; Fig. 1 C and D). proposition (Fig. 2A). rCNTF has been reported to substantially elevate SOCS3 expres- sion (45) and can induce regeneration if SOCS3
Load more

Recommended publications
  • Enhanced Monocyte Migration to CXCR3 and CCR5 Chemokines in COPD
    ERJ Express. Published on March 10, 2016 as doi: 10.1183/13993003.01642-2015 ORIGINAL ARTICLE IN PRESS | CORRECTED PROOF Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD Claudia Costa1, Suzanne L. Traves1, Susan J. Tudhope1, Peter S. Fenwick1, Kylie B.R. Belchamber1, Richard E.K. Russell2, Peter J. Barnes1 and Louise E. Donnelly1 Affiliations: 1Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK. 2Chest Clinic, King Edward King VII Hospital, Windsor, UK. Correspondence: Louise E. Donnelly, Airway Disease, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, UK. E-mail: [email protected] ABSTRACT Chronic obstructive pulmonary disease (COPD) patients exhibit chronic inflammation, both in the lung parenchyma and the airways, which is characterised by an increased infiltration of macrophages and T-lymphocytes, particularly CD8+ cells. Both cell types can express chemokine (C-X-C motif) receptor (CXCR)3 and C-C chemokine receptor 5 and the relevant chemokines for these receptors are elevated in COPD. The aim of this study was to compare chemotactic responses of lymphocytes and monocytes of nonsmokers, smokers and COPD patients towards CXCR3 ligands and chemokine (C-C motif) ligand (CCL)5. Migration of peripheral blood mononuclear cells, monocytes and lymphocytes from nonsmokers, smokers and COPD patients toward CXCR3 chemokines and CCL5 was analysed using chemotaxis assays. There was increased migration of peripheral blood mononuclear cells from COPD patients towards all chemokines studied when compared with nonsmokers and smokers. Both lymphocytes and monocytes contributed to this enhanced response, which was not explained by increased receptor expression.
    [Show full text]
  • S41467-017-02610-0.Pdf
    ARTICLE DOI: 10.1038/s41467-017-02610-0 OPEN Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours Adama Sidibe 1,4, Patricia Ropraz1, Stéphane Jemelin1, Yalin Emre 1, Marine Poittevin1, Marc Pocard2,3, Paul F. Bradfield1 & Beat A. Imhof1 1234567890():,; Recruitment of circulating monocytes is critical for tumour angiogenesis. However, how human monocyte subpopulations extravasate to tumours is unclear. Here we show mechanisms of extravasation of human CD14dimCD16+ patrolling and CD14+CD16+ inter- mediate proangiogenic monocytes (HPMo), using human tumour xenograft models and live imaging of transmigration. IFNγ promotes an increase of the chemokine CX3CL1 on vessel lumen, imposing continuous crawling to HPMo and making these monocytes insensitive to chemokines required for their extravasation. Expression of the angiogenic factor VEGF and the inflammatory cytokine TNF by tumour cells enables HPMo extravasation by inducing GATA3-mediated repression of CX3CL1 expression. Recruited HPMo boosts angiogenesis by secreting MMP9 leading to release of matrix-bound VEGF-A, which amplifies the entry of more HPMo into tumours. Uncovering the extravasation cascade of HPMo sets the stage for future tumour therapies. 1 Department of Pathology and Immunology, Centre Médical Universitaire (CMU), Medical faculty, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland. 2 Department of Oncologic and Digestive Surgery, AP-HP, Hospital Lariboisière, 2 rue Ambroise Paré, F-75475 Paris cedex 10, France. 3 Université Paris Diderot, Sorbonne Paris Cité, CART, INSERM U965, 49 boulevard de la Chapelle, F-75475 Paris cedex 10, France. 4Present address: Department of Physiology and Metabolism, Centre Médical Universitaire (CMU), Medical faculty, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland.
    [Show full text]
  • Lung Adenocarcinoma-Intrinsic GBE1 Signaling Inhibits Anti-Tumor Immunity
    Li et al. Molecular Cancer (2019) 18:108 https://doi.org/10.1186/s12943-019-1027-x RESEARCH Open Access Lung adenocarcinoma-intrinsic GBE1 signaling inhibits anti-tumor immunity Lifeng Li1,3,4,5†, Li Yang1,3,4†, Shiqi Cheng1,3,4†, Zhirui Fan3, Zhibo Shen1,3,4, Wenhua Xue2, Yujia Zheng1,3,4, Feng Li1,3,4, Dong Wang1,3,4, Kai Zhang1,3,4, Jingyao Lian1,3,4, Dan Wang1,3,4, Zijia Zhu2, Jie Zhao2,5,6* and Yi Zhang1,3,4* Abstract Background: Changes in glycogen metabolism is an essential feature among the various metabolic adaptations used by cancer cells to adjust to the conditions imposed by the tumor microenvironment. Our previous study showed that glycogen branching enzyme (GBE1) is downstream of the HIF1 pathway in hypoxia-conditioned lung cancer cells. In the present study, we investigated whether GBE1 is involved in the immune regulation of the tumor microenvironment in lung adenocarcinoma (LUAD). Methods: We used RNA-sequencing analysis and the multiplex assay to determine changes in GBE1 knockdown cells. The role of GBE1 in LUAD was evaluated both in vitro and in vivo. Results: GBE1 knockdown increased the expression of chemokines CCL5 and CXCL10 in A549 cells. CD8 expression correlated positively with CCL5 and CXCL10 expression in LUAD. The supernatants from the GBE1 knockdown cells increased recruitment of CD8+ T lymphocytes. However, the neutralizing antibodies of CCL5 or CXCL10 significantly inhibited cell migration induced by shGBE1 cell supernatants. STING/IFN-I pathway mediated the effect of GBE1 knockdown for CCL5 and CXCL10 upregulation. Moreover, PD-L1 increased significantly in shGBE1 A549 cells compared to those in control cells.
    [Show full text]
  • Review of Dendritic Cells, Their Role in Clinical Immunology, and Distribution in Various Animal Species
    International Journal of Molecular Sciences Review Review of Dendritic Cells, Their Role in Clinical Immunology, and Distribution in Various Animal Species Mohammed Yusuf Zanna 1 , Abd Rahaman Yasmin 1,2,* , Abdul Rahman Omar 2,3 , Siti Suri Arshad 3, Abdul Razak Mariatulqabtiah 2,4 , Saulol Hamid Nur-Fazila 3 and Md Isa Nur Mahiza 3 1 Department of Veterinary Laboratory Diagnosis, Faculty of Veterinary Medicine, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia; [email protected] 2 Laboratory of Vaccines and Biomolecules, Institute of Bioscience, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia; [email protected] (A.R.O.); [email protected] (A.R.M.) 3 Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia; [email protected] (S.S.A.); [email protected] (S.H.N.-F.); [email protected] (M.I.N.M.) 4 Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia * Correspondence: [email protected]; Tel.: +603-8609-3473 or +601-7353-7341 Abstract: Dendritic cells (DCs) are cells derived from the hematopoietic stem cells (HSCs) of the bone marrow and form a widely distributed cellular system throughout the body. They are the most effi- cient, potent, and professional antigen-presenting cells (APCs) of the immune system, inducing and dispersing a primary immune response by the activation of naïve T-cells, and playing an important role in the induction and maintenance of immune tolerance under homeostatic conditions. Thus, this Citation: Zanna, M.Y.; Yasmin, A.R.; review has elucidated the general aspects of DCs as well as the current dynamic perspectives and Omar, A.R.; Arshad, S.S.; distribution of DCs in humans and in various species of animals that includes mouse, rat, birds, dog, Mariatulqabtiah, A.R.; Nur-Fazila, cat, horse, cattle, sheep, pig, and non-human primates.
    [Show full text]
  • Bioinformatics Identification of CCL8/21 As Potential Prognostic
    Bioscience Reports (2020) 40 BSR20202042 https://doi.org/10.1042/BSR20202042 Research Article Bioinformatics identification of CCL8/21 as potential prognostic biomarkers in breast cancer microenvironment 1,* 2,* 3 4 5 1 Bowen Chen , Shuyuan Zhang ,QiuyuLi, Shiting Wu ,HanHe and Jinbo Huang Downloaded from http://portlandpress.com/bioscirep/article-pdf/40/11/BSR20202042/897847/bsr-2020-2042.pdf by guest on 28 September 2021 1Department of Breast Disease, Maoming People’s Hospital, Maoming 525000, China; 2Department of Clinical Laboratory, Maoming People’s Hospital, Maoming 525000, China; 3Department of Emergency, Maoming People’s Hospital, Maoming 525000, China; 4Department of Oncology, Maoming People’s Hospital, Maoming 525000, China; 5Department of Medical Imaging, Maoming People’s Hospital, Maoming 525000, China Correspondence: Shuyuan Zhang ([email protected]) Background: Breast cancer (BC) is the most common malignancy among females world- wide. The tumor microenvironment usually prevents effective lymphocyte activation and infiltration, and suppresses infiltrating effector cells, leading to a failure of the host toreject the tumor. CC chemokines play a significant role in inflammation and infection. Methods: In our study, we analyzed the expression and survival data of CC chemokines in patients with BC using several bioinformatics analyses tools. Results: The mRNA expression of CCL2/3/4/5/7/8/11/17/19/20/22 was remark- ably increased while CCL14/21/23/28 was significantly down-regulated in BC tis- sues compared with normal tissues. Methylation could down-regulate expression of CCL2/5/15/17/19/20/22/23/24/25/26/27 in BC. Low expression of CCL3/4/23 was found to be associated with drug resistance in BC.
    [Show full text]
  • Association of Chemokine CCL5 and Systemic Malignancies
    J Hum Genet (2008) 53:377–378 DOI 10.1007/s10038-008-0270-6 LETTER TO THE EDITOR Association of chemokine CCL5 and systemic malignancies Shailendra Kapoor Received: 28 January 2008 / Accepted: 8 February 2008 / Published online: 27 March 2008 Ó The Japan Society of Human Genetics and Springer 2008 To the Editor CCL5 levels are also increased in a wide spectrum of The article by Konta et al. (2008) on the relationship other diseases, such as idiopathic inflammatory myopathies between CC chemokine ligand 5 (CCL5) genotype and (Civatte et al. 2005) and chronic gastritis (Ohtani et al. urinary albumin excretion in the nondiabetic Japanese 2004). The recent study by Konta et al. further adds to general population is highly interesting. The study by diseases in which CCL5 plays a major pathogenetic role. Konta et al. adds to the growing array of pathological Further studies are needed to identify potent and safe conditions in which CCL5 plays a major role. Interestingly, inhibitors of CCL5 for better management of these diseases CCL5 has recently been implicated in the etiopathogenesis ranging from breast cancer to nondiabetic albuminuria. of a number of systemic malignancies. For instance, Luboshits et al. (1999), in a recent study, have shown that advanced breast cancers are associated References with increased expression of CCL5. CCL5 has also been shown to be a significant predictor of progression in Aldinucci D, Lorenzon D, Cattaruzza L, Pinto A, Gloghini A, Carbone A, Colombatti A (2008) Expression of CCR5 receptors patients with stage II breast cancer (Hahoshen et al. 2006). on Reed-Sternberg cells and Hodgkin lymphoma cell lines: In another study, tumors that expressed higher levels of involvement of CCL5/Rantes in tumor cell growth and micro- CCL5 were more likely to metastasize in comparison with environmental interactions.
    [Show full text]
  • The Role of Interleukin-1 Cytokine Family (IL-1Β, IL-37) and Interleukin-12 Cytokine
    bioRxiv preprint doi: https://doi.org/10.1101/502609; this version posted December 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Title: 2 The Role of Interleukin-1 cytokine family (IL-1β, IL-37) and interleukin-12 cytokine 3 family (IL-12, IL-35) in eumycetoma infection pathogenesis. 4 5 6 Authors 7 Amir Abushouk1,2, Amre Nasr1,2,3, Emad Masuadi4, Gamal Allam5,6, Emmanuel E. Siddig7, 8 Ahmed H. Fahal7 9 10 1Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdul-Aziz 11 University for Health Sciences, Jeddah, Kingdom of Saudi Arabia. E. mail: shouka@ksau- 12 hs.edu.sa 13 14 2King Abdullah International Medical Research Centre, National Guard Health Affairs, 15 Kingdom of Saudi Arabia. 16 17 3Department of Microbiology, College of Sciences and Technology, Al-Neelain University, 18 P.O. Box 1027, Khartoum, Sudan. [email protected] 19 20 4Research Unit, Department of Medical Education, College of Medicine-Riyadh, King Saud 21 Bin Abdul-Aziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia. E. mail: 22 [email protected] 23 bioRxiv preprint doi: https://doi.org/10.1101/502609; this version posted December 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Chemokines As the Modulators of Endometrial Epithelial Cells
    www.nature.com/scientificreports Corrected: Author Correction OPEN Chemokines as the modulators of endometrial epithelial cells remodelling Received: 27 February 2019 A Złotkowska & A Andronowska Accepted: 23 August 2019 Previous studies highlighted chemokines as potential factors regulating changes in the endometrium Published online: 10 September 2019 during early pregnancy. The current study aimed to screen the efects of a broad range of chemokines and indicate those that are involved in porcine luminal epithelial (LE) cell remodelling. Messenger RNA expression of chemokines (CCL2, CCL4, CCL5, CCL8, CXCL2, CXCL8, CXCL10 and CXCL12) and both the mRNA and protein expression of their receptors (CCR1, CCR2, CCR3, CCR5, CXCR2, CXCR3, CXCR4) were detected in LE cells. Exogenous CCL8 enhanced the proliferative and migration potential of LE cells and their motility in the environment with its stable concentration. The adhesive properties of LE cells were negatively afected by CCL8. However, CXCL12 positively afected the proliferation, motility and adhesion of LE cells as well as caused a decrease in MUC1 mRNA expression. To conclude, our studies determined that exogenous chemokines afected critical endometrial epithelial cell functions in the context of embryo implantation. We suggest that of all the examined factors, chemokine CCL8 participates in the establishment of a proper environment for embryo implantation, whereas CXCL12, apart from participation in endometrial receptivity, promotes embryo attachment. Pregnancy proceeds diferently depending on the species. In pigs, the peri-implantation period, when embryo mortality is the highest (approximately 30%), decides the success of a pregnancy1. Enhanced foetal loss dur- ing the mentioned period happens when there is inappropriate embryo development or disrupted communi- cation between mother and embryo, which can be the efect of inadequate endometrial preparation for embryo attachment2.
    [Show full text]
  • Critical Role of CXCL4 in the Lung Pathogenesis of Influenza (H1N1) Respiratory Infection
    ARTICLES Critical role of CXCL4 in the lung pathogenesis of influenza (H1N1) respiratory infection L Guo1,3, K Feng1,3, YC Wang1,3, JJ Mei1,2, RT Ning1, HW Zheng1, JJ Wang1, GS Worthen2, X Wang1, J Song1,QHLi1 and LD Liu1 Annual epidemics and unexpected pandemics of influenza are threats to human health. Lung immune and inflammatory responses, such as those induced by respiratory infection influenza virus, determine the outcome of pulmonary pathogenesis. Platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) has an immunoregulatory role in inflammatory diseases. Here we show that CXCL4 is associated with pulmonary influenza infection and has a critical role in protecting mice from fatal H1N1 virus respiratory infection. CXCL4 knockout resulted in diminished viral clearance from the lung and decreased lung inflammation during early infection but more severe lung pathology relative to wild-type mice during late infection. Additionally, CXCL4 deficiency decreased leukocyte accumulation in the infected lung with markedly decreased neutrophil infiltration into the lung during early infection and extensive leukocyte, especially lymphocyte accumulation at the late infection stage. Loss of CXCL4 did not affect the activation of adaptive immune T and B lymphocytes during the late stage of lung infection. Further study revealed that CXCL4 deficiency inhibited neutrophil recruitment to the infected mouse lung. Thus the above results identify CXCL4 as a vital immunoregulatory chemokine essential for protecting mice against influenza A virus infection, especially as it affects the development of lung injury and neutrophil mobilization to the inflamed lung. INTRODUCTION necrosis factor (TNF)-a, interleukin (IL)-6, and IL-1b, to exert Influenza A virus (IAV) infections cause respiratory diseases in further antiviral innate immune effects.2 Meanwhile, the innate large populations worldwide every year and result in seasonal immune cells act as antigen-presenting cells and release influenza epidemics and unexpected pandemic.
    [Show full text]
  • Metastasis: Active Lymph Nodes
    RESEARCH HIGHLIGHTS METASTASIS subcapsular sinus. Further investiga- tions in vivo revealed that CCR8 acti- vation in tumour cells was required Active lymph nodes for tumour cell extravasation from lymphatic vessels, specifically for the Lymph node metastases are CCL1 activates CCR8-mediated transmigration of tumour cells from indicative of poor prognosis but intracellular signalling in tumour the subcapsular sinus into the lymph tumour cell the mechanisms of tumour cell cells, which resulted in cellular node cortex. entry into the dissemination via the lymphatics changes that are consistent with cell These data unpick the process of are poorly understood. Although it migration. lymphatic dissemination and iden- lymph node is widely believed that tumour cells Is the CCR8–CCL1 paracrine tify the sequence of steps leading to requires active enter the lymph nodes passively with pathway important in lymphatic lymph node metastasis. The authors cell migration the flow of lymph, previous data have metastasis? The suppression of showed that CCR8 is expressed by indicated that some chemokines may CCR8 expression or activity in a large subset of human melanoma promote lymphatic extravasation human melanoma cells did not samples, and it will be interesting and metastasis. Das et al. now dem- affect tumour growth or vasculariz­ to determine whether this pathway onstrate that tumour cell entry into ation on implantation into immuno­ can be targeted to prevent lymph the lymph node requires active cell deficient mice, but significantly node metastasis. migration and they also identify the reduced the incidence of lymph Gemma K. Alderton lymphatic endothelium of the lymph node metastasis. Furthermore, ORIGINAL RESEARCH PAPER Das, S.
    [Show full text]
  • Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1
    pathogens Article Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1 Acacia F. Dishman 1,2,†, Jie He 3,†, Brian F. Volkman 1,* and Anna R. Huppler 3,* 1 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA; [email protected] 2 Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA 3 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; [email protected] * Correspondence: [email protected] (B.F.V.); [email protected] (A.R.H.) † These authors contributed equally. Abstract: Candida species cause serious infections requiring prolonged and sometimes toxic therapy. Antimicrobial proteins, such as chemokines, hold great interest as potential additions to the small number of available antifungal drugs. Metamorphic proteins reversibly switch between multiple different folded structures. XCL1 is a metamorphic, antimicrobial chemokine that interconverts between the conserved chemokine fold (an α–β monomer) and an alternate fold (an all-β dimer). Previous work has shown that human XCL1 kills C. albicans but has not assessed whether one or both XCL1 folds perform this activity. Here, we use structurally locked engineered XCL1 variants and Candida killing assays, adenylate kinase release assays, and propidium iodide uptake assays to demonstrate that both XCL1 folds kill Candida, but they do so via different mechanisms. Our results suggest that the alternate fold kills via membrane disruption, consistent with previous work, and the chemokine fold does not. XCL1 fold-switching thus provides a mechanism to regulate Citation: Dishman, A.F.; He, J.; the XCL1 mode of antifungal killing, which could protect surrounding tissue from damage associ- Volkman, B.F.; Huppler, A.R.
    [Show full text]
  • Fas Ligand Elicits a Caspase-Independent Proinflammatory Response in Human Keratinocytes: Implications for Dermatitis Sherry M
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Serveur académique lausannois ORIGINAL ARTICLE See related commentary on pg 2364 Fas Ligand Elicits a Caspase-Independent Proinflammatory Response in Human Keratinocytes: Implications for Dermatitis Sherry M. Farley1, Anjali D. Dotson1, David E. Purdy1, Aaron J. Sundholm1, Pascal Schneider2, Bruce E. Magun1 and Mihail S. Iordanov1 Fas ligand (FasL) causes apoptosis of epidermal keratinocytes and triggers the appearance of spongiosis in eczematous dermatitis. We demonstrate here that FasL also aggravates inflammation by triggering the expression of proinflammatory cytokines, chemokines, and adhesion molecules in keratinocytes. In HaCaT cells and in reconstructed human epidermis (RHE), FasL triggered a NF-kB-dependent mRNA accumulation of inflammatory cytokines (tumor necrosis factor-a, IL-6, and IL-1b), chemokines (CCL2/MCP-1, CXCL1/GROa, CXCL3/GROg, and CXCL8/IL-8), and the adhesion molecule ICAM-1. Oligomerization of Fas was required both for apoptosis and for gene expression. Inhibition of caspase activity abolished FasL-dependent apoptosis; however, it failed to suppress the expression of FasL-induced genes. Additionally, in the presence of caspase inhibitors, but not in their absence, FasL triggered the accumulation of CCL5/RANTES (regulated on activation normal T cell expressed and secreted) mRNA. Our findings identify a novel proinflammatory role of FasL in keratinocytes that is independent of caspase activity and is separable from apoptosis. Thus, in addition to causing spongiosis, FasL may play a direct role in triggering and/or sustaining inflammation in eczemas. Journal of Investigative Dermatology (2006) 126, 2438–2451. doi:10.1038/sj.jid.5700477; published online 20 July 2006 INTRODUCTION increased local concentration of procaspase 8 allows for Apoptosis (Kerr et al., 1972), the principal mechanism for its spontaneous autocatalytic cleavage and activation by elimination of damaged cells in metazoan organisms (Edinger ‘‘induced proximity’’ (Muzio et al., 1998).
    [Show full text]