Differential peritoneal resident macrophage depletion and omental milky spot disruption after high versus low clodronate‐loaded liposome dose treatment

Clodronate-loaded liposomes (CL liposomes) have been widely employed to deplete different macrophage subpopulations to assess their role in homeostatic, repair, regulatory, defense, autoimmune and inflammatory processes. Administration of CL liposomes, while promoting macrophage killing, can have long-term anti-inflammatory effects or cause inflammation in several mouse disease models. Therefore, the collateral effects of CL liposome treatment need to be explored when designing experiments involving macrophage depletion by CL liposomes. In this regard, the effect of a standard (high) versus low CL liposome dose on peritoneal macrophage kinetics and the structural integrity of the omentum has been investigated. High-dose clodronate treatment led to a long-lasting resMØ depletion but induced peritoneal inflammation and caused a severe and persistent omental milky spot disorganization, precluding drawing definitive conclusions on peritoneal resMØs function. In contrast, low-dose clodronate led to a transient depletion of resMØs but did not promote significant milky spot alterations or peritoneal inflammation, thus ensuring an efficient resMØ depletion in the absence of severe collateral effects, yet during a limited time window. These results have important implications for the design of experimental models aiming at addressing the role of peritoneal macrophages in peritoneal bacterial infection and tumor metastasis based on their depletion by CL liposomes.