Experimental Abdominal Aortic Aneurysm Formation Is Mediated by IL-17 and Attenuated by Mesenchymal Stem Cell Treatment

Abstract

Background Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation and matrix degradation. This study tests the hypothesis that CD4+ T cell-produced IL-17 modulates inflammation and smooth muscle cell activation leading to the pathogenesis of AAA and that human mesenchymal stem cell (MSC) treatment can attenuate IL-17 production and AAA formation. Methods and Results Human aortic tissue demonstrated a significant increase in IL-17 and IL-23 expression in AAA patients compared to controls as analyzed by RT-PCR and ELISA. AAA formation was assessed in C57BL/6 (wild type; WT), IL-23−/− or IL-17−/− mice using an elastase-perfusion model. Heat-inactivated elastase was used as control. On days 3, 7 and 14 following perfusion, abdominal aorta diameter was measured by video micrometry, and aortic tissue was analyzed for cytokines, cell counts and IL-17-producing CD4+ T cells. Aortic diameter and cytokine production (MCP-1, RANTES, KC, TNF-α, MIP-1α and IFN-γ) was significantly attenuated in elastase-perfused IL-17−/− and IL-23−/− mice compared to WT mice on day 14. Cellular infiltration (especially IL-17-producing CD4+ T cells) was significantly attenuated in elastase-perfused IL-17−/− mice compared to WT mice on day 14. Primary aortic smooth muscle cells were significantly activated by elastase or IL-17 treatment. Furthermore, MSC treatment significantly attenuated AAA formation and IL-17 production in elastase-perfused WT mice. Conclusion These results demonstrate that CD4+ T cell-produced IL-17 plays a critical role in promoting inflammation during AAA formation and that immunomodulation of IL-17 by MSCs can offer protection against AAA formation.

Inhibiting the Th17/IL-17A–Related Inflammatory Responses With Digoxin Confers Protection Against Experimental Abdominal Aortic Aneurysm

“…As reported by Sharma et al, 15 IL-17 plays a critical role in promoting inflammation during AAA formation. However, in a recent study performed by Ziad Mallat et al, overexpression of suppressor of cytokine signaling 3 in T cells and neutralization of TGF-β activity markedly reduced IL-17 production and increased the aneurysm severity.…”

GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency

“…Since CD4 + T cells are divided into Th1, Th2, Th17, Th22, and Th9 (24), and most studies focused only on Th1 (secreting IFN-γ) and Th17 (secreting IL-17), which are believed to predominantly contribute to the pathological changes in autoimmune and inflammatory aneurysm (25,26), we selected IL-17 and IFN-γ for use in this study. First, we performed immunohistochemistry on our mouse samples and determined that IFN-γ and IL-17 were expressed in the inflammatory cells (Supplemental Figure 6A).Then, to investigate whether these cytokines play a role in our model, we crossed our mice into a C57BL/6 background for at least 6 generations and generated IFN-γ-and IL-17-deficient Smad3 +/-mice.…”

T lymphocytes and aortic aneurysms

“…The contribution of IL-17 in aneurysm development may be related to its role in modulating SMCs activation. Therefore, the depletion of IL-17 showed attenuated aortic diameter and cytokine production [46]. This theory was confirmed by Ju et al [47], who found that IL-6-signal transducer and activator of transcription-3 (IL-6-STAT3) signaling pathway contributed to Th17 recruitment, promoting aneurysm formation.…”

“…Accumulation of reports document that CD8 + T cells infiltrate aneurysm lesion both from human and mice tissues [13,14,17,26,31,46,54,[64][65][66][67][68][69][70][71]. The predominant cell types within the infiltrate in AAA tissues are CD3 + T cells (more than 50%), including CD4 + T cells and CD8 + T cells [17].…”