Human vascular smooth muscle cells utilise chymase for the atypical cleavage and activation of Interleukin-1β

Atherosclerosis and other cardiovascular diseases (CVD) are well established to be both instigated and worsened by inflammation. Indeed, CANTOS formally proved that targeting the inflammatory cytokine IL-1β only could reduce both cardiovascular events and death. However, due to the central role of IL-1β in host defence, blockade increased fatal infections, suggesting targeting key immune mediators over the long natural history of CVD is unsuitable. Thus, discovering alternative mechanisms that generate vascular inflammation may identify more actionable targets. We used primary human VSMCs and a combination of biochemical, pharmacological and molecular biological techniques to generate the data. Human carotid atherosclerotic plaques were also assessed histologically. We showed that VSMCs expressed and efficiently processed pro-IL-1β to the active form after receiving a single stimulus via IL-1R1 or TLR4. Importantly, pro-IL-1β processing did not utilise inflammasomes or caspases. Unusually, we found that cathepsin C-activated chymase was responsible for cleaving IL-1β in VSMCs, and provided evidence for chymase expression in cultured VSMCs and in the fibrous cap of human plaques. Chymase also efficiently cleaved and activated recombinant pro-IL-1β. Thus, VSMCs are efficient activators of IL-1β that do not use canonical inflammasomes or caspases. Hence, this alternative pathway could be targeted for long-term treatment of CVDs, as it is not central to everyday host defence. •Inflammation drives atherosclerosis, but long-term IL-1β blockade causes fatal infection.•Targeting IL-1β but allowing its normal immune role might alleviate this problem.•Human VSMCs efficiently activate pro-IL-1β, but do not use inflammasomes or caspases.•VSMCs unusually require only one signal to both express and cleave pro-IL-1β.•Chymase is the activator of pro-IL-1β in VSMCs and we show expression in plaques.