Macrophage Depletion Protects Against Cisplatin-Induced Ototoxicity and Nephrotoxicity

Abstract

Cisplatin is a widely used and highly effective anti-cancer drug with significant side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced ototoxicity and nephrotoxicity, we used PLX3397, an FDA-approved inhibitor of the colony-stimulating factor 1 receptor (CSF1R), to eliminate tissue-resident macrophages during the course of cisplatin administration. Mice treated with cisplatin alone (cisplatin/vehicle) had significant hearing loss (ototoxicity) as well as kidney injury (nephrotoxicity). Macrophage ablation using PLX3397 resulted in significantly reduced hearing loss measured by auditory brainstem responses (ABR) and distortion-product otoacoustic emissions (DPOAE). Sensory hair cells in the cochlea were protected against cisplatin-induced death in mice treated with PLX3397. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis as well as reduced plasma blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together our data indicate that ablation of tissue-resident macrophages represents a novel strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.Brief summaryMacrophage ablation using PLX3397 was protective against cisplatin-induced ototoxicity and nephrotoxicity by limiting platinum accumulation in the inner ear and kidney.

Toward systemic lipofuscin removal

“…Systemic depletion of TRMs could then potentially be effected via small molecule CSF1R inhibitors in combination with anti-CSF1R and anti-CD45 ADCs [53,[57][58][59][60][61][62][63][64][65]. If the HSCs are edited ex vivo, the CD45 ADC would also suffice as non-genotoxic conditioning for subsequent transplant [66].…”

Ex Vivo Tissue-Resident Macrophage Replacement Prior to Allogeneic Transplantation

“…Given a multi-day window of time, the donors tissue-resident macrophages (TRMs) could be depleted using PLX3397, a small molecule CSF1R inhibitor, and at least partially repopulated by "offthe-shelf" TRMs [4][5][6][7].…”

Towards periodic whole-body lipofuscin removal

“…In the future, the systemic depletion of tissue-resident macrophages (TRMs) could be effected via the CSF1R inhibitors, PLX3397 [90] and PLX5622 [91] -perhaps combined with an anti-CD45 immunotoxin [92]. PLX3397 has been tested in clinical trials [93], and PLX5622, an inhibitor that crosses the blood-brain barrier more efficiently than PLX3397, has been extensively tested in a preclinical context [94].…”