Abstract
Dendritic cells (DC), macrophages, and monocytes, collectively known as mononuclear phagocytes (MPs), critically control tissue homeostasis and immune defense. However, there is a paucity of models allowing to selectively manipulate subsets of these cells in specific tissues. The steady-state adult kidney contains four MP subsets with Clec9a-expression history that include the main conventional DC1 (cDC1) and cDC2 subtypes as well as two subsets marked by CD64 but varying levels of F4/80. How each of these MP subsets contributes to the different phases of acute kidney injury and repair is unknown. We created a mouse model with a Cre-inducible lox-STOP-lox-diphtheria toxin receptor cassette under control of the endogenous CD64 locus that allows for diphtheria toxin-mediated depletion of CD64-expressing MPs without affecting cDC1, cDC2, or other leukocytes in the kidney. Combined with specific depletion of cDC1 and cDC2, we revisited the role of MPs in cisplatin-induced kidney injury. We found that the intrinsic potency reported for CD11c+ cells to limit cisplatin toxicity is specifically attributed to CD64+ MPs, while cDC1 and cDC2 were dispensable. Thus, we report a mouse model allowing for selective depletion of a specific subset of renal MPs. Our findings in cisplatin-induced injury underscore the value of dissecting the functions of individual MP subsets in kidney disease, which may enable therapeutic targeting of specific immune components in the absence of general immunosuppression.
Highlights
Dendritic cells (DC), macrophages, and monocytes, collectively known as mononuclear phagocytes (MPs), critically control tissue homeostasis and immune defense
We have shown that 3 d after cisplatin treatment, kidneys contain five populations with prominent Clec9a-expression history: conventional DC1 (cDC1), cDC2, CD11bhi, and F4/80hi cells as well as a small population of MHCIInegF4/80hi cells that arises from down-regulation of MHCII on F4/80hi cells [9]
Clec9a-expression history was found in cDC1, cDC2, CD11bhi, and F4/80hi cells 48 h after cisplatin treatment but MHCIInegF4/80hi cells were barely detectable at this time (SI Appendix, Fig. S1 A–C and F)
Summary
Dendritic cells (DC), macrophages, and monocytes, collectively known as mononuclear phagocytes (MPs), critically control tissue homeostasis and immune defense. F4/80hi MPs phenotypically and transcriptionally resemble embryonic-derived macrophages [9, 10] in adulthood they acquire prominent Clec9a-expression history [9] Because their affiliation as macrophages or DCs remains controversial [9,10,11,12,13,14,15], we refer to these cells as F4/80hi MPs. Cell depletion using “pan-macrophage” and “pan-DC” models that would affect multiple kidney MP subsets has shown that MPs are critically involved in kidney immune defense and contribute to kidney injury and subsequent tissue repair [4, 13, 16, 17]. Defining the functions of specific subsets of MPs in kidney disease could help to dissect their contributions to kidney pathology and repair, which could subsequently be targeted for Significance
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