Author: Ghaemi Kerahrodi, Jasmin ; Luebber, Finn ; Aherrahrou, Zouhair ; Schulz, Andreas ; Brachaczek, Lukas ; Humrich, Jens Y ; Heidorn, Marc W ; Ten Cate, Vincent ; Grasshoff, Hanna ; Dechend, Ralf ; Pfeiffer, Norbert ; Müller, Felix S ; Schwarting, Andreas ; Schulze-Forster, Kai ; Wild, Philipp S ; Robles, Alejandro Pallares ; Reinberger, Tobias ; Aherrahrou, Redouane ; Erdmann, Jeanette ; Münzel, Thomas ; Lange, Tanja ; Lackner, Karl J ; Riemekasten, Gabriela ; Koeck, Thomas ; Tüscher, Oliver ; Prochaska, Jürgen H ; Heidecke, Harald ; Rapp, Steffen ; Johanson, Laurence ; Strauch, Konstantin

AbstractBackground and AimsChronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear.MethodsAnti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(−/−) mice for preclinical validation.ResultsThe analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima–media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine–cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(−/−) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model.ConclusionsIn individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

01 Jan 2020·Journal of Dermatological ScienceQ2 · MEDICINE

Activation of STING signaling accelerates skin wound healing

Q2 · MEDICINE

Article

Author: Ito, Hiroyasu ; Mizutani, Yuki ; Kanbe, Ayumu ; Seishima, Mariko

BACKGROUNDThe process of repair after skin injury is precisely regulated by a variety of mediators such as cytokines and chemokines. Recent reports demonstrated that cytoplasmic DNA-sensor cyclic GMP-AMP synthase (cGAS) activates the stimulator of interferon genes (STING) via production of cyclic GMP-AMP (cGAMP) and subsequently induces inflammatory cytokines, including type I interferon (IFN).OBJECTIVEWe examined whether activation of the STING pathway by cGAMP affects the process of skin wound repair.METHODSThe skin wound repair model was established using wild-type (WT) mice. Two full-thickness skin biopsies were taken from the right and left subscapular regions. One site was treated with ointment containing cGAMP, and the other was treated with a control ointment. Changes in wound size over time were calculated using photography.RESULTSTreatment with cGAMP significantly accelerated skin wound healing up to day 6. Biochemical analyses showed that topical treatment with cGAMP on wound sites promoted STING signaling pathway and enhanced the expression of IFN-β, CXCL10 and CCL2 in the wound sites treated with cGAMP markedly compared with the control. The scratch assay also revealed that cGAMP treatment accelerated wound closure in mouse embryonic fibroblasts. The acceleration of skin wound repair by cGAMP in WT mouse was impaired by administration of anti-IFNR antibody and anti-CXCR3 antibody respectively.CONCLUSIONThese results revealed that topical treatment with cGAMP accelerates skin wound healing by inducing type I IFN and CXCL10/CXCR3. Topical administration of cGAMP might contribute to new effective treatments for accelerating skin wound healing.

01 May 2018·Laboratory InvestigationQ2 · MEDICINE

Disruption of CXCR3 function impedes the development of Sjögren's syndrome-like xerostomia in non-obese diabetic mice

Q2 · MEDICINE

Article

Author: Yu, Qing ; Zhou, Jing

The chemokine receptor CXCR3 plays an important role in T cell recruitment in various immune responses and autoimmune diseases. Expression of CXCR3 ligands, including CXCL9, CXCL10, and CXCL11, is elevated in the salivary glands of patients with Sjögren's syndrome (SS). To elucidate whether interaction between CXCR3 and its ligands is required for the development of SS, we administrated an anti-CXCR3 blocking antibody (CXCR3-173) to the non-obese diabetic (NOD) mice, a well-defined model of SS, during the stage prior to disease onset. Treatment with this anti-CXCR3 antibody significantly improved salivary secretion, indicating a remission of SS clinical manifestation. Anti-CXCR3 treatment did not affect the gross leukocyte infiltration of the submandibular glands (SMGs) as assessed by hematoxylin and eosin staining. However, flow cytometric analysis showed that anti-CXCR3 treatment markedly reduced the percentage of CXCR3⁺CD8 T and CXCR3⁺CD44⁺CD8 T cells, without affecting that of CXCR3⁺CD4 T and CXCR3⁺CD44⁺CD4 T cells in the SMGs and submandibular lymph nodes, suggesting a preferential effect of this anti-CXCR3 treatment on CXCR3-expressing effector CD8 T cells. Meanwhile, SMG expression of inflammatory factor TNF-α was markedly diminished by anti-CXCR3 treatment. In accordance, anti-CXCR3 significantly enhanced SMG expression of tight junction protein claudin-1 and water channel protein aquaporin 5, two molecules that are crucial for normal salivary secretion and can be down-regulated by TNF-α. Taken together, these findings demonstrated that the interaction between the endogenous CXCR3 and its ligands plays a pro-inflammatory and pathogenic role in the development of SS-like xerostomia in the NOD mouse model.

100 Deals associated with Anti-CXCR3 mAb (Monash University)

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Preclinical	AU	Monash University	-
Graft Rejection	Preclinical	AU	Monash University	-
Nonalcoholic Steatohepatitis	Preclinical	AU	Monash University	-
Diabetes Mellitus, Type 1	Discovery	AU	Monash University	-
Graft vs Host Disease	Discovery	AU	Monash University	-
Inflammatory Bowel Diseases	Discovery	AU	Monash University	-

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