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Updated: Aug 12, 2025
Porcine Model of Infrarenal Abdominal Aortic Aneurysm
Published on: November 21, 2019
Interleukin-38 suppresses abdominal aortic aneurysm formation in mice by regulating macrophages in an IL1RL2-p38
Shun Kurose1, Yutaka Matsubara1, Shinichiro Yoshino1
1Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abstract:
Macrophages play crucial roles in abdominal aortic aneurysm (AAA) formation through the inflammatory response and extracellular matrix degradation; therefore, regulating macrophages may suppress AAA formation. Interleukin-38 (IL-38) is a member of the IL-1 family, which binds to IL-36 receptor (IL1RL2) and has an anti-inflammation effect. Because macrophages express IL1RL2, we hypothesized that IL-38 suppresses AAA formation by controlling macrophages. We assessed a C57BL6/J mouse angiotensin II-induced AAA model with or without IL-38 treatment. RAW 264.7 cells were cultured with tumor necrosis factor-α and treated with or without IL-38. Because p38 has important roles in inflammation, we assessed p38 phosphorylation in vitro and in vivo. To clarify whether the IL-38 effect depends on the p38 pathway, we used SB203580 to inhibit p38 phosphorylation. IL1RL2+ macrophage accumulation along with matrix metalloproteinase (MMP)-2 and -9 expression was observed in mouse AAA. IL-38 reduced the incidence of AAA formation along with reduced M1 macrophage accumulation and MMP-2 and -9 expression in the AAA wall. Macrophage activities including inducible nitric oxide, MMP-2, and MMP-9 production and spindle-shaped changes were significantly suppressed by IL-38. Furthermore, we revealed that inhibition of p38 phosphorylation diminished the effects of IL-38 on regulating macrophages to reduce AAA incidence, indicating the protective effects of IL-38 depend on the p38 pathway. IL-38 plays protective roles against AAA formation through regulation of macrophage accumulation in the aortic wall and modulating the inflammatory phenotype. Using IL-38 may be a novel therapy for AAA patients.
Insights
Interleukin-38 (IL-38) suppresses abdominal aortic aneurysm (AAA) formation by regulating macrophages via the p38 pathway. This finding suggests IL-38 as a potential novel therapy for AAA patients.
Area of Science:
- Immunology
- Vascular Biology
- Pharmacology
Background:
- Macrophages are key drivers of abdominal aortic aneurysm (AAA) pathogenesis through inflammation and extracellular matrix degradation.
- Interleukin-38 (IL-38), an IL-1 family member, exhibits anti-inflammatory properties by binding to IL-36 receptor (IL1RL2).
- Macrophages express IL1RL2, suggesting a potential role for IL-38 in modulating macrophage-driven AAA formation.
Purpose of the Study:
- To investigate the hypothesis that IL-38 suppresses AAA formation by regulating macrophage activity.
- To elucidate the role of the p38 signaling pathway in mediating the effects of IL-38 on macrophages and AAA.
- To explore the therapeutic potential of IL-38 in AAA.
Main Methods:
- An angiotensin II-induced AAA mouse model (C57BL6/J) was used, with and without IL-38 treatment.
- RAW 264.7 macrophage cell line was stimulated with tumor necrosis factor-α and treated with IL-38.
- p38 phosphorylation was assessed in vitro and in vivo; p38 inhibition was achieved using SB203580.
Main Results:
- IL-38 treatment reduced AAA incidence, M1 macrophage accumulation, and matrix metalloproteinase (MMP)-2 and -9 expression in the AAA wall.
- IL-38 significantly suppressed macrophage activities, including inducible nitric oxide, MMP-2, and MMP-9 production, and morphological changes.
- Inhibition of p38 phosphorylation attenuated the IL-38-mediated regulation of macrophages and reduction in AAA incidence, confirming the dependence on the p38 pathway.
Conclusions:
- IL-38 exerts protective effects against AAA formation by modulating macrophage accumulation and inflammatory phenotype in the aortic wall.
- The anti-AAA effects of IL-38 are dependent on the p38 signaling pathway.
- IL-38 represents a promising therapeutic target for managing abdominal aortic aneurysms.
