Sung, C. Y. W. | Search bioRxiv

bioRxiv2023

Macrophage Depletion Protects Against Cisplatin-Induced Ototoxicity and Nephrotoxicity

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.

immunology↗

bioRxiv2022

Cytomegalovirus infection in newborn mice alters cerebellar development by lengthening G1/S phases of cerebellar granule cell precursors during postnatal cerebellar development

Human cytomegalovirus (HCMV) infection of the developing central nervous system (CNS) in infants infected in utero can lead to a variety of neurodevelopmental disorders. Although the link between HCMV infection and neurodevelopmental deficits is widely recognized, underlying mechanisms leading to altered neurodevelopment remain poorly understood. We have previously described a murine model of congenital HCMV infection in which murine CMV (MCMV) spreads hematogenously and establishes a focal infection in the brain of newborn mice. Infection results in the disruption of cerebellar cortical development characterized by reduced cerebellar size, but paradoxically, an increase in the number of cerebellar granule cell precursors (GCPs) in the external granular layer (EGL) of the cerebellar cortex. This increased number of GCPs in the EGL is associated with abnormal cell cycle progression and decreased GCP migration from EGL and IGL. In the current study, we demonstrated that MCMV infection led to prolonged G1- and S-phases of the GCP cell cycle and increased cell cycle exit. Treatment with TNF neutralizing antibody partially normalized the cell cycle progression of GCPs. Collectively, our results argue that inflammation can alter GCP proliferation and lead to premature exit from the cell cycle resulting in reduced cerebellar size in MCMV-infected mice. These findings provide insight into mechanisms of altered brain development of fetuses infected with HCMV and possibly, other infectious agents that induce inflammation during neurodevelopment.

developmental biology↗