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Resident macrophages reprogram toward a developmental state after acute kidney injury
Jeremie M Lever1,2, Travis D Hull3, Ravindra Boddu1,2
1Department of Medicine and.
Abstract:
Acute kidney injury (AKI) is a devastating clinical condition affecting at least two-thirds of critically ill patients, and, among these patients, it is associated with a greater than 60% risk of mortality. Kidney mononuclear phagocytes (MPs) are implicated in pathogenesis and healing in mouse models of AKI and, thus, have been the subject of investigation as potential targets for clinical intervention. We have determined that, after injury, F4/80hi-expressing kidney-resident macrophages (KRMs) are a distinct cellular subpopulation that does not differentiate from nonresident infiltrating MPs. However, if KRMs are depleted using polyinosinic/polycytidylic acid (poly I:C), they can be reconstituted from bone marrow-derived precursors. Further, KRMs lack major histocompatibility complex class II (MHCII) expression before P7 but upregulate it over the next 14 days. This MHCII- KRM phenotype reappears after injury. RNA sequencing shows that injury causes transcriptional reprogramming of KRMs such that they more closely resemble that found at P7. KRMs after injury are also enriched in Wingless-type MMTV integration site family (Wnt) signaling, indicating that a pathway vital for mouse and human kidney development is active. These data indicate that mechanisms involved in kidney development may be functioning after injury in KRMs.
Insights
Kidney-resident macrophages (KRMs) are distinct cells that do not infiltrate during acute kidney injury (AKI). These KRMs can be replenished from bone marrow precursors and show developmental gene expression after injury.
Area of Science:
- Nephrology
- Immunology
- Developmental Biology
Background:
- Acute kidney injury (AKI) affects critically ill patients, leading to high mortality.
- Kidney mononuclear phagocytes (MPs) play roles in AKI pathogenesis and healing.
- Understanding kidney-resident macrophages (KRMs) is crucial for AKI therapeutic strategies.
Purpose of the Study:
- To characterize kidney-resident macrophages (KRMs) in the context of acute kidney injury (AKI).
- To investigate the origin and developmental characteristics of KRMs after kidney injury.
Main Methods:
- Utilized mouse models of AKI.
- Employed F4/80hi expression to identify KRMs.
- Depletion and reconstitution experiments using polyinosinic/polycytidylic acid (poly I:C).
- Analyzed major histocompatibility complex class II (MHCII) expression and RNA sequencing.
Main Results:
- Identified F4/80hi KRMs as a distinct subpopulation, not derived from infiltrating MPs.
- Demonstrated KRM reconstitution from bone marrow precursors upon depletion.
- Observed MHCII expression upregulation in KRMs post-injury, resembling early developmental stages (P7).
- RNA sequencing revealed transcriptional reprogramming and enrichment of Wnt signaling in injured KRMs.
Conclusions:
- KRMs are a unique cell population in AKI, distinct from infiltrating monocytes.
- Kidney injury reactivates developmental pathways, including Wnt signaling, in KRMs.
- These findings suggest developmental mechanisms are repurposed in KRMs during kidney repair.
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