Macrophage TBK1 promotes tubular endoplasmic reticulum stress via proinflammatory cytokines in cisplatin-induced acute kidney injury.

Cisplatin-induced acute kidney injury (AKI) is driven by inflammation and endoplasmic reticulum (ER) stress, yet the upstream immune mechanisms remain unclear. Macrophages are keymediatorsof renal inflammation, and TANK-binding kinase 1 (TBK1) is an important regulator of inflammatory signaling. However, whether macrophage TBK1 promotes tubular injury bydrivinga proinflammatory cascade has not been defined. We showed that TBK1 was robustly activated in the kidneys following cisplatin injury and predominantly co-localized with macrophages. Myeloid-specific TBK1 deficiency attenuated tubular damage, suppressed proinflammatory molecules expression, inhibited PERK/eIF2α/ATF4/CHOP ER stress pathway, and reduced apoptosis. Notably, cisplatin treatment sharply increased F4/80+-TNF-α+ cells in injured kidneys, a population markedly diminished in mice devoid of myeloid TBK1. In vitro, macrophages deficient in TBK1 secreted significantly lower levels of proinflammatory cytokines upon cisplatin stimulation, and their conditioned medium elicited less ER stress and apoptosis in HK-2 cells, with a concomitant suppression of the PERK/eIF2α/ATF4/CHOP cascade. Critically, replenishment of exogenous TNF-α to this medium fully restored these deleterious effects, along with reactivation of this pathway. Finally, pharmacological TBK1 inhibition with GSK8612 similarly protected against cisplatin nephropathy, reducing kidney injury, ER stress, and apoptosis. In summary, macrophage TBK1 activation drives inflammatory crosstalk, promoting ER stress and apoptosis in tubular epithelial cells during cisplatin-induced AKI. Thus, targeting TBK1 may represent a promising therapeutic strategy for cisplatin nephropathy.