CCL17-deficiency results in increased infarct volume and increased Th1 and Th17 immune cell polarisation after experimental stroke

Jan-Kolja Strecker, Antje Schmidt, Irmgard Förster, Kai Diederich, Judith Alferink Jens Minnerup1

Abstract

Introduction: Following cerebral ischemia, a plethora of immune cells like functional diverse T cell subsets contribute to both, beneficial and deleterious effects during the progressing damage development. The role of dendritic cells (DCs), which activate T cells, has not been determined within strokes pathology. DCs, which express the chemokine CCL17, are known to be key regulators of Th17 and Treg cell function. The role of CCL17 and the DC-dependent immunomodulation within the pathogenesis of the ischemic stroke are subject of this presentation. Methods: Transient middle cerebral ischemia was induced by occlusion of the middle cerebral artery (MCAO, 30 min) in CCL17-deficient, heterozygous and wildtype mice. Furthermore, CCL17/WT and WT/CCL17-bone marrow chimeras were generated. Following MCAO, mice were tested for functional outcome, infarct volume, CCL17 expression, expression of Th1/M1-, Th2/M2-, Th17 and Treg-gene expression and presence as well as activation state of immune cells by immunofluorescence analysis and flow cytometry. Results: Cerebral ischemia led to worsened functional outcome (p<0.001) and increased infarct lesion size (p<0.05) in CCL17-deficient mice. Immunofluorescence analysis revealed CCL17 expression by neurons and immigrated hematogenous cells. CCL17-deficient brains showed increased neutrophil immigration and increased expression of Th1- and Th17-related Genes. Restimulated Splenocytes showed increased TNF-alpha production. Analysis of bone-marrow chimeras further suggests a neuroprotective role of neuronal expressed CCL17. Conclusion: These results suggest a neuroprotective role of CCL17 within the pathogenesis of ischemia/reperfusion damage.