Doxorubicin triggers splenic contraction and irreversible dysregulation of COX and LOX that alters inflammation-resolution program in the myocardium

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-months-old male C57BL/6J mice were divided into high and low dose DOX-treated groups maintaining saline control. The first group was injected with high DOX 15mg/kg/week (H-DOX) and the second group was injected with 7.5mg/kg/week as latent low DOX (LL-DOX). Given that H-DOX led to complete mortality in two weeks and 70% survival in LL-DOX were compared with saline controls. Therefore, additional group of mice were injected with acute high DOX (AH-DOX) that were sacrificed at 24h in order to compare with LL-DOX and saline controls. The LL-DOX and AH-DOX showed obvious apoptosis, dysfunctional, and structural changes in cardiac tissue. The splenic contraction was evident in AH- and LL-DOX treated mice indicating the systems-wide impact of DOX on integrative organs of the spleen which is essential for cardiac homeostasis and repair. DOX dysregulated splenic enriched immune sensitive lipoxygenase (LOX) and cyclooxygenase (COX) in the spleen and left ventricle (LV) compared with saline controls. As a result, LOX dependent D- and E-series resolvin precursors such as 16HDoHE, 4HDoHE, and 12-HEPE and COX-mediated PGs species (PGD2, PGE2, and 6-keto-PG2α) were decreased in the LV suggestive of defective immunometabolism. Both AH- and LL-DOX-induced splenic contraction and expansion of red pulp with decreased CD169+ metallophilic macrophages. AH-DOX intoxicated the macrophages in the spleen by depleting CD169+ cells in the acute setting and sustained the splenic macrophage loss in chronic phase in LL-DOX. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity thereby impaired inflammation-resolution program.