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

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.