Structure and Function of Renal Macrophages and Dendritic Cells From Lupus‐Prone Mice

Abstract

Objective To characterize renal macrophages and dendritic cells in two murine lupus nephritis models. Methods We used a bead based enrichment step followed by cell sorting to isolate populations of interest from young and nephritic mice. Cell morphology was examined by microscopy. Arginase and nitrite production were examined using biochemical assays. Antigen presentation function was determined using mixed lymphocyte reactions. Selected cytokine, chemokine and TLR profiles were examined using quantitative real time PCR. Results We identified two populations of macrophages and three populations of dendritic cells in both SLE models. F4/80hi macrophages, that are normal kidney residents and increase during nephritis, do not produce either arginase or nitrite upon cytokine stimulation and acquire a mixed pro and anti-inflammatory functional phenotype during nephritis that resembles the constitutively activated phenotype of gut F4/80hi macrophages. The various cell types differ in their expression of chemokine receptors and TLRs, consistent with variability in their renal location. Resident renal CD103+ DCs are the best antigen-presenting cells and can easily be distinguished from CD11chi myeloid DCs that accumulate in large numbers during nephritis. Conclusions Our study highlights the heterogeneity of the macrophage/DC infiltrate in chronic SLE nephritis and provides an initial phenotypic and functional analysis of the different cellular components that can now be used to define the role of each subset in nephritis progression or amelioration. Of note, the dominant macrophage population that accumulates during nephritis has an acquired phenotype that is neither M1 nor M2 and may reflect failure of resolution of inflammation.

RNA sensing by conventional dendritic cells is central to the development of lupus nephritis

“…These were originally described as a tissue-resident sentinel DC population; however, our data strongly support their reclassification as macrophages based on gene-expression profiling (31,54,55 (33).…”

“…It is unclear whether the CD11c + F4/80 + cells present in all strains are either macrophages or DCs. They were originally described as a kidney resident sentinel DC (31), but more recently they were reclassified as macrophages based on their morphological and functional features (32,33). Therefore, to confirm the ontogeny of these and our novel infiltrating CD11c…”

Anti-C1q Autoantibodies from Systemic Lupus Erythematosus Patients Induce a Proinflammatory Phenotype in Macrophages

“…In fact, no characteristic macrophage phenotype could be defined in lupus nephritis. Different reports showed that infiltrating macrophages/DCs in murine lupus nephritis are very heterogeneous (42,43). Nevertheless, mononuclear cells play a role in the pathogenesis of organ-related diseases, such as lupus nephritis, and are associated with chronic tissue damage and injury (44).…”

“…Infiltration of mononuclear cells plays a role in the progression of lupus nephritis and is associated with poor prognosis in SLE patients (45). Data from murine models of lupus nephritis suggest that macrophages and DCs infiltrating the kidneys represent a heterogeneous group and are derived from circulating peripheral monocytes (42,43). Sahu et al (42) found that the dominant macrophage subtype was not M1 or M2 and concluded that this phenotype might reflect an overall failure to resolve inflammation present in kidneys during flares.…”

“…Data from murine models of lupus nephritis suggest that macrophages and DCs infiltrating the kidneys represent a heterogeneous group and are derived from circulating peripheral monocytes (42,43). Sahu et al (42) found that the dominant macrophage subtype was not M1 or M2 and concluded that this phenotype might reflect an overall failure to resolve inflammation present in kidneys during flares. Additionally, the onset of proliferative glomerulonephritis in mice was associated with an upregulation of chemokine and cytokine expression, mediating further infiltration of activated DCs and monocytes into the kidneys.…”