PCSK9 and Inflammation: Their Role in Autoimmune Diseases, with a Focus on Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Despite a clear epidemiological link between autoimmune disease and cardiovascular (CV) risk exists, pathophysiological explanations are extremely complex and far from being elucidated. Dysregulation of metabolic pathways and chronic low-grade inflammation represent common pathways, but CV risk still remains underestimated in patients with autoimmune diseases. Among different candidate mediators, pro-protein convertase subtilisin/kexin type 9 (PCSK9) is attracting growing attention, due to a combined effect on lipid metabolism and inflammatory response. Studies on PCSK9 inhibitors have established a clear benefit on CV outcome without an established effect on inflammation. Conversely, evidence from sepsis and HIV infection strongly supports a pro-inflammatory role of PCSK9. Still, the role of PCSK9 in autoimmune diseases is uncertain. So far, reported clinical findings are controversial and likely reflect the poor knowledge of PCSK9 activity on monocyte/macrophage migration and activation. The complex signaling network around PCSK9 synthesis and metabolism may also have a role, especially concerning the involvement of scavenger receptors, such as CD36. Such complexity in PCSK9 signaling seems particularly evident in autoimmune disease model. This would also potentially explain the observed independency between lipid profile and PCSK9 levels, the so-called "lipid paradox". In this narrative review, we will summarize the current knowledge about the complex network of PCSK9 signaling. We will focus on upstream and downstream pathways with potential implication in autoimmune disease and potential effects of PCSK9 inhibiting strategies.