The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice

Abstract

Although the pathogenesis of abdominal aortic aneurysm (AAA) remains unclear, evidence is accumulating to support a central role for inflammation. Inflammatory responses are coordinated by various soluble cytokines of which IL-6 is one of the major proinflammatory cytokines. In this study we examined the role of IL-6 in the pathogenesis of experimental AAA induced by a periaortic exposure to CaCl2 in mice. We now report that the administration of MR16-1, a neutralizing monoclonal antibody specific for the mouse IL-6 receptor, mildly suppressed the development of AAA. The inhibition of IL-6 signaling provoked by MR16-1 also resulted in a suppression of Stat3 activity. Conversely, no significant changes in either NFκB activity, Jnk activity or the expression of matrix metalloproteinases (Mmp) -2 and -9 were identified. Transcriptome analyses revealed that MR16-1-sensitive genes encode chemokines and their receptors, as well as factors that regulate vascular permeability and cell migration. Imaging cytometric analyses then consistently demonstrated reduced cellular infiltration for MR16-1-treated AAA. These results suggest that IL-6 plays an important but limited role in AAA pathogenesis, and primarily regulates cell migration and infiltration. These data would also suggest that IL-6 activity may play an important role in scenarios of continuous cellular infiltration, possibly including human AAA.

Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm

“…Consistent with that finding, compared to WT AAA tissues, muMT AAA tissues showed less significant expression of MMP9, an ECM protease that is regulated by Jnk in AAA, and a more significant increase in the expression of lysyl oxidase (Lox), an ECM‐synthesizing enzyme that can ameliorate AAA development . The observed changes in the protein expressions were specific to CaCl 2 challenge because they were not observed in sham‐operated mice, confirming the results of our previous article that saline treatment did not induce strong inflammation or AAA formation . These results indicated that a B‐cell deficiency resulted in the suppression of inflammatory signaling pathways including Syk and impeded development of AAA, possibly by suppressing ECM destruction and enhancing ECM synthesis.…”

“…This treatment caused chronic local inflammation, as described previously . We previously confirmed that the local inflammation was not elicited by a sham operation in which physiological saline had been used instead of CaCl 2 . Mice were killed with a pentobarbital overdose, and blood and tissue samples were collected at 2 time points: at 7 days after the CaCl 2 treatment and at 42 days after the CaCl 2 treatment.…”

“…Continued expressions were specific to CaCl 2 challenge because they were not observed in sham-operated mice, confirming the results of our previous article that saline treatment did not induce strong inflammation or AAA formation. 23 These results indicated that a B-cell deficiency resulted in the suppression of inflammatory signaling pathways including Syk and impeded development of AAA, possibly by suppressing ECM destruction and enhancing ECM synthesis.…”

“…17 We previously confirmed that the local inflammation was not elicited by a sham operation in which physiological saline had been used instead of CaCl 2 . 23 Mice were killed with a pentobarbital overdose, and blood and tissue samples were collected at 2 time points: at 7 days after the CaCl 2 treatment and at 42 days after the CaCl 2 treatment. Aortic tissue was excised either immediately, for protein and mRNA expression analyses, or after perfusion and fixation with 4% paraformaldehyde in phosphate-buffered saline at physiological pressure, for histological analysis.…”

Cytokines at the Interplay Between Asthma and Atherosclerosis?

“…Further to this, the balance between IL-6 and antiinflammatory IL-10 is believed to influence lipid homeostasis, plaque formation, and plaque morphology in mice (Schieffer et al, 2004). IL-6 is also well associated with abdominal aortic aneurysm (AAA) pathogenesis, primarily through modulating cell migration and infiltration (Nishihara et al, 2017). To date, however, IL-6 targeting has not been tested in secondary prevention of atherosclerosis and a phase 2a study, designed to evaluate the effects of sirukumab (human anti IL-6 monoclonal antibody) in subjects with severe poorly controlled asthma, was withdrawn (ClinicalTrials.gov Identifier: NCT02794519).…”