Monocyte/macrophage pyroptosis and C5b-9-induced cyst enlargement in Pkd1-/- mice

The levels of C5b-9, terminal products of complement activation, were significantly elevated in autosomal dominant polycystic kidney disease (ADPKD). However, the precise mechanisms by which C5b-9 facilitates cyst growth remain incompletely elucidated.

Three groups of chronic-onset Pkd1-/- mice were established: one group received intravenous injections of 0.5 mg/kg C5b-9, another was administered 1.0 mg/kg monoclonal anti-C9 antibodies, and a control group received 1 mg/kg IgG isotype control. All treatments were administered biweekly for two months (postnatal day 180-240). Renal macrophages from distinct subsets were sorted using fluorescence-activated cell sorting. To deplete macrophages, liposome clodronate was injected intraperitoneally. Sublethal irradiation followed by bone marrow reconstruction was performed in Pkd1-/- mice to evaluate the role of bone marrow-derived macrophages (BMDMs) in ADPKD progression.

(i) In vitro, sublytic C5b-9 did not affect the viability of renal tubular epithelial cells, but significantly induced M1-like polarization and pyroptosis of BMDMs. (ii) In vivo, C5b-9 notably triggered pyroptosis of Ly6C+ monocytes and a reduction in circulating monocyte numbers as cysts enlarged. (iii) Residual Ly6C+ monocytes infiltrated renal tissues and differentiated into Ly6C+ macrophages, which exhibited a greater susceptibility to pyroptosis compared to Ly6C- macrophages. (iv) Although limited evidence has recently suggested that Ly6C- monocytes may also be affected by C5b-9, upregulation of CCR2 in Ly6C- macrophages was observed in C5b-9-treated Pkd1-/- mice, implying that Ly6C- monocytes could represent a significant source of M2 macrophages.

C5b-9 infusion promoted renal tubular epithelial cell proliferation by inducing pyroptosis of Ly6C+ monocytes/macrophages, contributing to progressive cyst enlargement in chronic-onset PKD mice.