Selective depletion of a CD64-expressing phagocyte subset mediates protection against toxic kidney injury and failure

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.

Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy

“…Such a definition has limitations and may not be tenable in the dynamics of acute disorders with changing microenvironments when cell types exhibit phenotypic plasticity, and lineage tracing-related definitions are less valuable. However, it has become clear that MP subtypes have specific functions in pathology (22,23). Defining cell types by lineagespecific transcription factors is a powerful tool to establish the functions of MP in immunity.…”

Novel anti-inflammatory effects of the IL-1 receptor in kidney myeloid cells following ischemic AKI

“…Among kidney myeloid cells, macrophages and dendritic cells play important roles during both the initial injury and subsequent healing process. Unlike in other tissue microenvironments where CD11c (gene name Itgax ) is used to specifically identify dendritic cells, most non-neutrophil myeloid cells, including macrophages and some monocytes, express CD11c + ( Kawakami et al, 2013 ; Lever et al, 2019 ; Salei et al, 2020 ; Zimmerman et al, 2020 ; Salei et al, 2021 ; Privratsky et al, 2023 ). The roles of CD11c-expressing myeloid cells during AKI are complex and context-specific as CD11c + myeloid cells promote cyst formation in a cystic disease model ( Zimmerman et al, 2019 ); whereas deletion of CD11c + cells aggravates cisplatin- and sepsis-induced AKI ( Tadagavadi and Reeves, 2010 ; Privratsky et al, 2023 ), and impairs the healing process and promotes pro-inflammatory cytokine generation following ischemic AKI ( Kim et al, 2010 ; Lu et al, 2012 ).…”

Guidelines for DC preparation and flow cytometry analysis of mouse nonlymphoid tissues

“…We have recently revisited the role of MPs in cisplatin‐induced kidney injury using cell type‐specific depletion models. We found that the intrinsic potency reported for CD11c + cells to limit cisplatin toxicity is specifically attributed to CD64 + DC, while cDC1 and cDC2 are dispensable [120]. In nephrotoxic nephritis on the other hand, it has been shown that cDC1 protect the tissue, while cDC2 seem to play a pro‐inflammatory role [121, 122].…”