Emerging cytokines contribute to the clinical manifestation of carotid artery plaque formation and stability in patients with diabetes.

BACKGROUND

Type 2 diabetes mellitus (T2DM) promotes atherosclerosis and plaque instability through chronic inflammation and immune dysregulation. Emerging evidence implicates members of the interleukin-1 family-particularly IL-36, IL-37, and IL-38-in the modulation of inflammatory responses in diabetic and non-diabetic vascular disease. However, their roles in carotid atherosclerosis remain poorly defined.

METHODS

In this retrospective observational study, circulating cytokine levels were assessed in 20 T2DM and 40 non-DM individuals using ELISA. Carotid plaque samples (n = 50) were collected from endarterectomy procedures and categorised as stable (asymptomatic, n = 25) or unstable (symptomatic, n = 25) according to AHA criteria. Immunohistochemistry quantified local expression of IL-36α, IL-36β, IL-36γ, IL-37, and IL-38.

RESULTS

Circulating IL-36α, IL-36β and IL-36γ were significantly elevated in T2DM patients, while IL-37 and IL-38 levels were unchanged. Immunohistochemistry revealed significantly increased expression of all five cytokines in unstable versus stable plaques. Stratification by diabetic status showed that this upregulation was exclusive to diabetic patients. Notably, IL-36β exhibited the most pronounced increase-over 25-fold-in unstable diabetic plaques. IL-37 and IL-38 were also elevated locally, likely reflecting compensatory anti-inflammatory responses, though their circulating levels remained unaffected.

CONCLUSIONS

This study demonstrates differential expression of IL-36, IL-37, and IL-38 in carotid atherosclerotic plaques, with IL-36β emerging as a key pro-atherogenic cytokine in the diabetic setting. The distinct expression patterns of these cytokines in diabetic versus non-diabetic plaques suggest that T2DM exacerbates immune imbalance in atherosclerosis. These findings may inform future research on cytokine-targeted therapies for diabetic vascular complications.