Inclisiran Reduces Expression of Toll-like Receptor-4 on Circulating Monocytes

Background Toll-like receptor 4 (TLR4) is a key regulator of both innate and adaptive immune responses and its functions affects the initiation and progression of atherosclerosis. In addition, it has recently been shown that TLR4 regulates foam cell formation by catabolism of aggregated LDL and that TLR4 is induced by proprotein convertase subtilisin/kexin type 9 (PCSK9) in vitro. The aim of this study was to examine the effects of siRNA-induced knockdown of PCSK9 by inclisiran on the expression of TLR4 in vivo. Methods Patients on stable lipid lowering therapy for at least 4 weeks were treated with a single dose of inclisiran (284 mg s. c.) and blood samples were taken directly before treatment and after 1 and 3 months. Monocyte expression of TLR4 was analyzed by flow-cytometry. Results We included 22 consecutive patients, 54.5% of patients were male and median age was 63 (IQR 60-75) years. 15 patients were treated with high dose statin and 7 patients did not tolerate statin treatment. At baseline TLR4 expression tended to be lower in statin-treated patients (MFI: 2136 IQR 1427-4011 vs. 3115 IQR 2187 vs. 5851; p=0.06). TLR4 expression after one month was comparable to baseline. However, 3 months after after inclisiran treatment, TLR4 expression on monocytes significantly decreased as compared to baseline expression (MFI baseline: 2396 IQR 1802-4408; MFI 3 months: 1575 IQR 1263-2233; p=0.006). This effect was more pronounced in statin-naïve as compared to statin-treated patients (TLR4 MFI 3 months vs baseline no statin: -58.8 IQR -41.9 to -81.2 %; statin: -27.1 IQR +2.2 to -42.1 %). Conclusions siRNA-induced knockdown of PCSK9 by inclisiran was associated with significant decreased expression of TLR4 on circulating monocytes. This effect was more pronounced in patients with statin intolerance.