Abstract: TH-PO048
Annexin A1 Promotes the Resolution of Inflammation in Murine Crescentic Glomerulonephritis
Session Information
- Glomerular: Basic/Experimental Immunology and Inflammation - I
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Glomerular
- 1001 Glomerular: Basic/Experimental Immunology and Inflammation
Authors
- Labes, Robert, Charité Universitätsmedizin Berlin, Berlin, Germany
- Mrowka, Ralf, Friedrich-Schiller-Universität, KIM III, Jena, Germany
- Hugo, Christian, University of Dresden, Dresden, Germany, Dresden, SN, Germany
- Bachmann, Sebastian, Charité Universitätsmedizin Berlin, Berlin, Germany
- Von Vietinghoff, Sibylle, Hannover Medical School, Hannover, Germany
- Paliege, Alexander, University of Dresden, Dresden, Germany, Dresden, SN, Germany
Background
Resolution of acute inflammation occurs in an active and tightly regulated process which involves the suppression of pro-inflammatory signals and a cessation of leukocyte influx. The glucocorticoid-inducible protein annexin A1 has been suggested to function as key-regulator of the resolution process but its role in acute crescentic glomerulonephritis has not been studied so far.
Methods
Acute crescentic nephritis was induced in annexin A1 deficient (n=8) and wildtype mice (n=8) using a sheep serum raised against rat glomerular basement membrane constituents. Animals were sacrificed 10 days after induction of the nephritis. Renal morphology was analyzed using routine histological techniques. Renal leukocyte abundance was studied by fluorescence activated cell sorting (FACS). Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry.
Results
Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1 deficient mice as compared to the wildtype controls. FACS analysis confirmed an increased number of CD11b+/Gr1+ myeloid cells (+ 110 ± 32%; p < .01). Lipid mass spectrometry showed elevated levels of the proinflammatory prostaglandins PGE2 (+140 ± 62%, p < .05), and PGD2 (+78 ± 39%, p < .05) whereas the abundance of the anti-inflammatory and anti-fibrotic epoxy-derivates of docosapentaenoic acid (EDP) were reduced (10,11-EDP: -34 ± 2%; 13,14-EDP: -34 ± 5%; 16,17-EDP: -27 ± 4%; 19,20-EDP: -16 ± 5%; p < .05 each). RNA-Seq analysis demonstrated a higher abundance of several pro-inflammatory cytokines (IL-1b: +112 ± 62%; IL-5: +90 ± 29%; IL-6: +178 ± 58%; IL-12b: +70 ± 24%; IL-13: +260 ± 70%; TNF-:+82 ± 8%; p < .05 each) and Gene ontology analysis revealed induction of gene products related to neutrophil- (GO:0030593) and monocyte- (GO:0002548) chemotaxis (p < .01 each) .
Conclusion
Deficiency of annexin A1 results in a defective resolution process of renal inflammation with a persistence of pro-inflammatory signals, infiltration of myeloid cells, and aggravated tissue damage. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.
Funding
- Government Support - Non-U.S.