Characterization of kidney CD45intCD11bintF4/80+MHCII+CX3CR1+Ly6C- “intermediate mononuclear phagocytic cells”

Lee, Sul A; Noel, Sanjeev; Sadasivam, Mohanraj; Allaf, Mohamad E.; Pierorazio, Phillip M.; Hamad, Abdel R.A.; Rabb, Hamid

doi:10.1371/journal.pone.0198608

Cited by 18 publications

(17 citation statements)

References 40 publications

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“…The reason for this discrepancy is derived from the difference in tissue monocyte-lineage of the depleted macrophage subtypes by the above two tools 42,43 . In our study, we found that CLs depleted most of Ly6C − macrophages and a small portion of Ly6C + macrophages, which is consistent with a recent study 44 . However, the relation between these subtypes is still unclear and further studies will be required for more precise depletion of macrophage subtypes.…”

Section: Discussionsupporting

confidence: 93%

Bone marrow-derived Ly6C− macrophages promote ischemia-induced chronic kidney disease

et al. 2019

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Macrophages play an important role in renal injury and repair after acute kidney injury (AKI) and the subsequent chronic kidney disease (CKD) that often results. However, as macrophages have a high degree of plasticity and heterogeneity, the function(s) of macrophage subtypes in AKI-to-CKD progression are not fully understood. Here, we focused on Ly6C − macrophages, which are derived from the embryonic yolk sac and post-development become resident in the kidneys. We found that C–C chemokine receptor type 2 (CCR2) deficiency, which blocks the migration of Ly6C + macrophages from the bone marrow to the sites of injury, alleviated ischemia-induced AKI in mice. Unexpectedly, though, CCR2 deficiency worsened the subsequent renal fibrosis, which was marked by notable intra-renal infiltration of Ly6C − macrophages. These Ly6C − macrophages were greater in number in both the acute and chronic phases after ischemia reperfusion (I/R) in kidneys of wild type (WT) mice, and we showed them to be derived from the bone marrow by bone marrow chimerism. Clodronate Liposomes (CLs)-mediated depletion of renal Ly6C − macrophages in CCR2 − /− mice or in WT mice after I/R alleviated the renal injury and fibrosis. On the contrary, adoptive transfer of Ly6C − macrophages from injured kidneys of WT mice into immune-deficient mice was sufficient to induce renal injury and fibrosis. Transcriptome sequencing of Ly6C − macrophages from injured kidneys revealed that they secreted various cytokines and growth factors, which were associated with the transdifferentiation of fibroblasts into myofibroblasts. This transdifferentiation effect was further supported by in vitro studies showing that Ly6C − macrophages induced the secretion of extracellular matrix proteins from co-cultured fibroblasts. In conclusion, the presence of bone marrow-derived Ly6C − macrophages after ischemia induces AKI and worsens subsequent CKD.

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Section: Discussionsupporting

confidence: 93%

Bone marrow-derived Ly6C− macrophages promote ischemia-induced chronic kidney disease

et al. 2019

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“…Previous studies have administered higher doses of clodronate multiple times to achieve complete macrophage depletion 32 – 34 . In our model, liposomal clodronate at a single intraperitoneal dose of 200 ul significantly reduced blood monocytes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Kidney-resident macrophages promote a proangiogenic environment in the normal and chronically ischemic mouse kidney

Puranik

Leaf

Jensen

et al. 2018

Sci Rep

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Renal artery stenosis (RAS) caused by narrowing of arteries is characterized by microvascular damage. Macrophages are implicated in repair and injury, but the specific populations responsible for these divergent roles have not been identified. Here, we characterized murine kidney F4/80+CD64+ macrophages in three transcriptionally unique populations. Using fate-mapping and parabiosis studies, we demonstrate that CD11b/cint are long-lived kidney-resident (KRM) while CD11chiMϕ, CD11cloMϕ are monocyte-derived macrophages. In a murine model of RAS, KRM self-renewed, while CD11chiMϕ and CD11cloMϕ increased significantly, which was associated with loss of peritubular capillaries. Replacing the native KRM with monocyte-derived KRM using liposomal clodronate and bone marrow transplantation followed by RAS, amplified loss of peritubular capillaries. To further elucidate the nature of interactions between KRM and peritubular endothelial cells, we performed RNA-sequencing on flow-sorted macrophages from Sham and RAS kidneys. KRM showed a prominent activation pattern in RAS with significant enrichment in reparative pathways, like angiogenesis and wound healing. In culture, KRM increased proliferation of renal peritubular endothelial cells implying direct pro-angiogenic properties. Human homologs of KRM identified as CD11bintCD11cintCD68+ increased in post-stenotic kidney biopsies from RAS patients compared to healthy human kidneys, and inversely correlated to kidney function. Thus, KRM may play protective roles in stenotic kidney injury through expansion and upregulation of pro-angiogenic pathways.

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“…To evaluate the phenotype and function of donor rMFs after reversible I/RI, we used a model of congeneic renal transplantation. Compared with models of I/RI obtained by clamping the renal artery, 33,44 this method allowed us to discriminate between renal mononuclear-phagocytes from the donor and those derived from recipient monocytes infiltrating the graft at reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c+F4/80+ Macrophages through IL-1R8 Regulation

Aiello

Podestà

Rodriguez-Ordonez

et al. 2020

JASN

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BackgroundIn donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in controlling inflammation and fibrosis. No data are currently available regarding the effects of transplant-induced ischemia-reperfusion injury on the ability of donor-derived resident renal macrophages to act as professional antigen-presenting cells.MethodsWe evaluated the phenotype and function of intragraft CD11c+F4/80+ renal macrophages after cold ischemia. We also assessed the modifications of donor renal macrophages after reversible ischemia-reperfusion injury in a mouse model of congeneic renal transplantation. To investigate the role played by IL-1R8, we conducted in vitro and in vivo studies comparing cells and grafts from wild-type and IL-R8–deficient donors.ResultsCold ischemia and reversible ischemia-reperfusion injury dampened antigen presentation by renal macrophages, skewed their polarization toward the M2 phenotype, and increased surface expression of IL-1R8, diminishing activation mediated by toll-like receptor 4. Ischemic IL-1R8–deficient donor renal macrophages acquired an M1 phenotype, effectively induced IFNγ and IL-17 responses, and failed to orchestrate tissue repair, resulting in severe graft fibrosis and aberrant humoral immune responses.ConclusionsIL-1R8 is a key regulator of donor renal macrophage functions after ischemia-reperfusion injury, crucial to guiding the phenotype and antigen-presenting role of these cells. It may therefore represent an intriguing pathway to explore with respect to modulating responses against autoantigens and alloantigens after kidney transplant.

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Characterization of kidney CD45intCD11bintF4/80+MHCII+CX3CR1+Ly6C- “intermediate mononuclear phagocytic cells”

Cited by 18 publications

References 40 publications

Bone marrow-derived Ly6C− macrophages promote ischemia-induced chronic kidney disease

Bone marrow-derived Ly6C− macrophages promote ischemia-induced chronic kidney disease

Kidney-resident macrophages promote a proangiogenic environment in the normal and chronically ischemic mouse kidney

Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c+F4/80+ Macrophages through IL-1R8 Regulation

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