INFLAMMATORY SIGNATURE AFTER LOW DOSE gamma-RADIATION IN MICE BRAIN AND GUT: SWITCH FROM THERAPEUTIC BENEFIT TO INFLAMMATION
EUROPEAN JOURNAL OF INFLAMMATION
Authors: Aravindan, S.; Natarajan, M.; Veeraraghavan, J.; Herman, T. S.; Aravindan, N.
Low dose gamma-radiation (LDIR) has been used as curative/adjuvant/palliative treatment modality for a variety of medical conditions. However, LDIR has been casually linked to NF kappa B activation and inflammation. Here, we investigated the kinetics of cyto/chemokines and their influence on inflammation in normal tissues after LDIR. C57BL/6 mice exposed to LDIR (2-50cGy) and sacrificed after 1 h-8 days were examined for alterations in 95 cyto/chemokines in brain and gut (QPCR profiling) and selectively validated by assessing secreted levels (ELISA). Kinetics of LDIR-induced inflammation was assessed using DNA fragmentation and histomorphological changes in brain and gut. LDIR induced a dose-dependent upregulation of cyto/chemokines after 2-50cGy in both brain and gut. Two genes, Csf3 and Tnf alpha, were upregulated in a 'dose- and tissue-independent' manner. Transcriptional kinetics revealed induction of more genes both in brain and gut in early response time (1-48 h) after LDIR. Conversely, only few genes upregulated and more genes downregulated in these tissues after extended response (4-8 days) period. DNA fragmentation and histomorphological analysis revealed consistent dose-, time-and tissue-dependent inflammation after LDIR. Also, serum levels of TNF-alpha, VEGFA, IFN-gamma, GM-CSF, MCP-1 reinstigates the inflammatory signature after LDIR. Together, these results suggest that LDIR significantly inflicts a dose- and tissue-dependent inflammation in normal tissues and this induced inflammation may equivocate over-time and, hence frequency of LDIR use may control the switch from therapeutic benefit to inflammatory response.
Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4(+) hemangiocytes
Authors: Jin, David K.; Shido, Koji; Kopp, Hans-Georg; Petit, Isabelle; Shmelkov, Sergey V.; Young, Lauren M.; Hooper, Andrea T.; Amano, Hideki; Avecilla, Scott T.; Heissig, Beate; Hattori, Koichi; Zhang, Fan; Hicklin, Daniel J.; Wu, Yan; Zhu, Zhenping; Dunn, Ashley; Salari, Hassan; Werb, Zena; Hackett, Neil R.; Crystal, Ronald G.; Lyden, David; Rafii, Shahin
The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4(+)VEGFR1(+) hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4(+)VEGFR1(+) hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2(-/-)Csf3(-/-)), profound impairment in neovascularization was detected in sKitL-deficient Mmp9(-/-) as well as thrombocytopenic Thpo(-/-) and TPO receptor-deficient (Mpl(-/-)) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo(-/-), Mpl(-/-) and Mmp9(-/-) mice. Transplantation of CXCR4(+)VEGFR1(+) hemangiocytes into Mmp9(-/-) mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4(+)VEGFR1(+) cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4(+)VEGFR1(+) hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF- 1 may be effective in restoring angiogenesis in individuals with vasculopathies.