Interleukin 12p40 Deficiency Promotes Abdominal Aortic Aneurysm by Activating CCN2/MMP2 Pathways

Abstract

Background Development of abdominal aortic aneurysm (AAA) is associated with proinflammatory cytokines including interleukin‐12 (IL12). Deficiency of interleukin 12p40 (IL12p40) increases localized fibrotic events by promoting TGFβ2 (transforming growth factor β)‐dependent anti‐inflammatory response. Here, we determined whether IL12p40 deficiency in apolipoprotein E‐/‐ mice attenuates the development of AAA by antagonizing proinflammatory response. Methods and Results Double knockout (DKO) mice were generated by crossbreeding IL12p40‐/‐ mice with apolipoprotein E‐/‐ mice (n=12). Aneurysmal studies were performed using angiotensin II (1 µg/kg/min; subcutaneous). Surprisingly, DKO mice did not prevent the development of AAA with angiotensin II infusion. Immunohistological analysis, however, showed distinct pathological features between apolipoprotein E‐/‐ and DKO mice. Polymerase chain reaction (7 day) and cytokine arrays (28 day) of the aortic tissues from DKO mice showed significantly increased expression of cytokines related to anti‐inflammatory response (interleukin 5 and interleukin 13), synthetic vascular smooth muscle cell phenotype (Activin receptor‐like kinase‐1 (ALK‐1), artemin, and betacellulin) and T helper 17‐associated response (4‐1BB, interleukin‐17e (Il17e) and Cd40 ligand (Cd‐40L)). Indeed, DKO mice exhibited increased expression of the fibro‐proteolytic pathway in the medial layer of aortae induced by cellular communication network factor 2 (CCN2) and Cd3+IL17+ cells compared with apolipoprotein E‐/‐ mice. Laser capture microdissection showed predominant expression of CCN2/TGFβ2 in the medial layer of human AAA. Finally, Ccn2 haploinsufficiency in the mice showed decreased AAA incidence in response to elastase infusion, associated with decreased matrix metalloproteinase‐2 expression. Conclusions Our study reveals novel roles for IL12p40 deficiency in inducing fibro‐proteolytic activities in the aneurysmal mouse model. Mechanistically, these effects of IL12p40 deficiency are mediated by CCN2/matrix metalloproteinase‐2 crosstalk in the medial layer of aneurysmal aortae.

Keywords

• abdominal aortic aneurysm
• CCN2
• IL12p40
• TGFβ2
• Th17