Dataset Information

Interleukin-22 Deficiency Reduces Angiotensin II-Induced Aortic Dissection and Abdominal Aortic Aneurysm in ApoE-/- Mice.

ABSTRACT:

Background

Our previous study showed that interleukin-22 (IL-22) levels were increased in patients with aortic dissection (AD). This study evaluated the effects of IL-22 on AD/abdominal aortic aneurysm (AAA) formation in angiotensin II (Ang II)-infused ApoE-/- mice.

Methods

ApoE-/- mice were treated with Ang II for 28 days, and IL-22 expression was examined. In addition, the effects of IL22 deficiency on AAA/AD formation induced by Ang II infusion in ApoE-/- mice were investigated. ApoE-/-IL-22-/- mice were transplanted with bone marrow cells isolated from ApoE-/- mice or ApoE-/-IL-22-/- mice, and AAA/AD formation was observed.

Results

IL-22 expression was increased in both the aortas and serum of ApoE-/- mice after Ang II infusion and was mainly derived from aortic CD4+ T lymphocytes (CD4+ TCs). IL-22 deficiency significantly reduced the AAA/AD formation as well as the maximal aortic diameter in Ang II-infused ApoE-/- mice. Decreased elastin fragmentation and reduced fibrosis were observed in the aortas of ApoE-/-IL-22-/- mice compared with ApoE-/- mice. The deletion of IL-22 also decreased aortic M1 macrophage differentiation, alleviated M1 macrophage-induced oxidative stress, and reduced aortic smooth muscle cell loss. Furthermore, M1 macrophage-induced oxidative stress was worsened and AAA/AD formation was promoted in ApoE-/-IL-22-/- mice that received transplanted bone marrow cells from ApoE-/- mice compared with those that were transplanted with bone marrow cells isolated from ApoE-/-IL-22-/- mice.

Conclusions

IL-22 deficiency inhibits AAA/AD formation by inhibiting M1 macrophage-induced oxidative stress. IL-22 potentially represents a promising new target for preventing the progression of AAA/AD.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8956387 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Interleukin-22 Deficiency Reduces Angiotensin II-Induced Aortic Dissection and Abdominal Aortic Aneurysm in ApoE-/- Mice.

Wang Yuan Y Li Juanjuan J Xu Yulin Y Liao Shichong S Song Junlong J Xu Zhiliang Z Wei Wen W Zhu Shan S

Oxidative medicine and cellular longevity 20220318

<h4>Background</h4>Our previous study showed that interleukin-22 (IL-22) levels were increased in patients with aortic dissection (AD). This study evaluated the effects of IL-22 on AD/abdominal aortic aneurysm (AAA) formation in angiotensin II (Ang II)-infused ApoE-/- mice.<h4>Methods</h4>ApoE-/- mice were treated with Ang II for 28 days, and IL-22 expression was examined. In addition, the effects of IL22 deficiency on AAA/AD formation induced by Ang II infusion in ApoE-/- mice were investigated ...[more]

PMID: 35340206

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Project description: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.

Project description:Rationale: The progressive disruption of extracellular matrix (ECM) proteins, particularly early elastin fragmentation followed by abnormalities in collagen fibril organization, are key pathological processes that contribute to dissecting abdominal aortic aneurysm (AAA) pathogenesis. Lysyl hydroxylase 1 (LH1) is essential for type I/III collagen intermolecular crosslinking and stabilization. However, its function in dissecting AAA has not been explored. Here, we investigated whether LH1 is significantly implicated in dissecting AAA progression and therapeutic intervention. Methods and Results: Sixteen-week-old male LH1-deficient and wild-type (WT) mice on the C57Bl/6NCrl background were infused with angiotensin II (Ang II, 1000 ng/kg per minute) via subcutaneously implanted osmotic pumps for 4 weeks. Ang II increased LH1 levels in the abdominal aortas of WT mice, whereas mice lacking LH1 developed dissecting AAA. To evaluate the related mechanism, we performed whole-transcriptomic analysis, which demonstrated that LH1 deficiency aggravated gene transcription alterations; in particular, the expression of thrombospondin-1 was markedly upregulated in the aortas of LH1-deficient mice. Furthermore, targeting thrombospondin-1 with TAX2 strongly inhibited the proinflammatory process, matrix metalloproteinase (MMP) activity and vascular smooth muscle cells (VSMCs) apoptosis, ultimately decreasing the incidence of dissecting AAA. Restoration of LH1 protein expression in LH1-deficient mice by intraperitoneal injection of an adeno-associated virus normalized thrombospondin-1 levels, subsequently alleviating dissecting AAA formation and preserving aortic structure and function. Consistently, in human AAA specimens, decreased LH1 expression was associated with increased thrombospondin-1 levels. Conclusions: LH1 deficiency contributes to dissecting AAA pathogenesis, at least in part, by upregulating thrombospondin-1 expression, which subsequently enables proinflammatory processes, MMP activation and VSMCs apoptosis. Our study provides evidence that LH1 is a potential critical therapeutic target for AAA.

Dataset Information

Interleukin-22 Deficiency Reduces Angiotensin II-Induced Aortic Dissection and Abdominal Aortic Aneurysm in ApoE-/- Mice.

Background

Methods

Results

Conclusions

Publications

Interleukin-22 Deficiency Reduces Angiotensin II-Induced Aortic Dissection and Abdominal Aortic Aneurysm in ApoE-/- Mice.

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