Macrophage Reprogramming via Targeted ROS Scavenging and COX-2 Downregulation for Alleviating Inflammation

Inflammation-related diseases affect large populationsof peoplein the world and cause substantial healthcare burdens, which resultsin significant costs in time, material, and labor. Preventing or relievinguncontrolled inflammation is critical for the treatment of these diseases.Herein, we report a new strategy for alleviating inflammation by macrophagereprogramming via targeted reactive oxygen species (ROS) scavengingand cyclooxygenase-2 (COX-2) downregulation. As a proof of concept,we synthesize a multifunctional compound named MCI containing a mannose-basedmacrophage targeting moiety, an indomethacin (IMC)-based segment forinhibiting COX-2, and a caffeic acid (CAF)-based section for ROS clearance.As revealed by a series of in vitro experiments,MCI could significantly attenuate the expression of COX-2 and thelevel of ROS, leading to M1 to M2 macrophage reprogramming, as evidencedby the reduction and the elevation in the levels of pro-inflammatoryM1 markers and anti-inflammatory M2 markers, respectively. Furthermore, in vivo experiments show MCI ' s promising therapeuticeffects on rheumatoid arthritis (RA). Our work illustrates the successof targeted macrophage reprogramming for inflammation alleviation,which sheds light on the development of new anti-inflammatory drugs.

Automated summary

We propose a new strategy for alleviating inflammation by reprogramming macrophages through targeted reactive oxygen species scavenging and cyclooxygenase-2 downregulation. Our multifunctional compound MCI successfully attenuates COX-2 expression and reduces the level of ROS, leading to macrophage reprogramming and decreased inflammation. In vivo experiments demonstrate the promising therapeutic effects of MCI on rheumatoid arthritis. This study presents the successful targeted macrophage reprogramming for inflammation alleviation and provides insights for the development of new anti-inflammatory drugs.