Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow–Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice

Abstract

Glomerular damage mediated by glomerulus-infiltrating myeloid-derived cells is a key pathogenic event in lupus nephritis (LN), but the process is poorly understood. Confocal microscopy of kidney sections and flow cytometry analysis of glomerular cells from magnetic bead-purified glomeruli have identified glomerulus-infiltrating leukocyte populations in NZM2328 (NZM) lupus-prone mice with spontaneous chronic glomerulonephritis (GN) and anti-glomerular basement membrane-induced nephritis. The occurrence of a major glomerulus-infiltrating CD11b⁺F4/80^-I-A^- macrophage population exhibiting the markers programmed death ligand-1 (PD-L1), Mac-2, and macrophage mannose receptor (CD206) and producing <i>Klf4</i>, <i>Il10</i>, <i>Retnla</i>, <i>Tnf</i>, and <i>Il6</i> mRNA, which are known to be expressed by alternatively activated (M2b) macrophages, correlated with proteinuria status. In NZM mice with spontaneous LN, glomerular macrophage infiltration is predominant. CD11b⁺F4/80^-I-A^- intraglomerular macrophages and polymorphonuclear neutrophils (PMN) are important in inducing GN, as anti-CD11b and -ICAM-1 mAb inhibited both proteinuria and macrophage and PMN infiltration. The predominant and high expression of PD-L1 by CD11b⁺F4/80^-I-A^- glomerular macrophages in kidneys of mice with GN and the inhibition of proteinuria by anti-PD-L1 mAb supported the pathogenic role of these macrophages but not the PD-L1^- PMN in GN development and in inducing podocyte damage. In NZM mice with spontaneous chronic GN and severe proteinuria, few glomerulus-infiltrating PMN were found, leaving macrophages and, to a less extent, dendritic cells as the major infiltrating leukocytes. Taken together, these data support the important pathogenic effect of CD11b⁺F4/80^-I-A^- M2b-like glomerulus-infiltrating macrophages in LN and reinforce macrophages as a promising target for GN treatment.