Inhibition of PI3Kδ Reduces Kidney Infiltration by Macrophages and Ameliorates Systemic Lupus in the Mouse

Abstract

Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease generated and maintained throughout life by autoreactive T and B cells. Class I phosphoinositide 3-kinases (PI3K) are heterodimers composed of a regulatory and a catalytic subunit that catalyze phosphoinositide-3,4,5-P3 formation and regulate cell survival, migration, and division. Activity of the PI3Kδ isoform is enhanced in human SLE patient PBLs. In this study, we analyzed the effect of inhibiting PI3Kδ in MRL/lpr mice, a model of human SLE. We found that PI3Kδ inhibition ameliorated lupus progression. Treatment of these mice with a PI3Kδ inhibitor reduced the excessive numbers of CD4+ effector/memory cells and B cells. In addition, this treatment reduced serum TNF-α levels and the number of macrophages infiltrating the kidney. Expression of inactive PI3Kδ, but not deletion of the other hematopoietic isoform PI3Kγ, reduced the ability of macrophages to cross the basement membrane, a process required to infiltrate the kidney, explaining MRL/lpr mice improvement by pharmacologic inhibition of PI3Kδ. The observations that p110δ inhibitor prolonged mouse life span, reduced disease symptoms, and showed no obvious secondary effects indicates that PI3Kδ is a promising target for SLE.

Microthrombotic Renal Vascular Lesions Are Associated to Increased Renal Inflammatory Infiltration in Murine Lupus Nephritis

“…An influx of activated macrophages can be seen in both murine and human LN (28–32), with macrophages accumulating peri- and intra-glomerularly (33, 34). In addition, pharmacological inhibition of macrophage infiltration in the kidney ameliorates SLE in mouse models (35). Our findings also evidence that macrophagic infiltration is the most consistent histological marker of inflammatory damage in MRL/lpr mice with LN and its accumulation correlates with the degree of proteinuria.…”

PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms

“…The first experiments investigating the role of PI3K in monocytes introduced antibodies specific to p110b or p110d into macrophages and specifically identified these PI3K isoforms as key regulators of migration downstream of the tyrosine kinase receptor for colony-stimulating factor-1 (CSF-1) (Vanhaesebroeck et al, 1999). More recently, a PI3Kd inhibitor reduced the number of macrophages infiltrating the kidney in systemic lupus erythematosus (Suarez-Fueyo et al, 2014). Concerning class IB isoforms, mice lacking PI3Kg were shown to present a decrease in neutrophil and macrophage recruitment in a model of peritonitis induced by bacterial injection (Hirsch et al, 2000).…”

Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells

“…To measure ECM degradation, we stained collagen IV in BM and quantified intensity using the ImageJ [50]; DAPI intensity was used to normalize values. Pan02 cells degraded less collagen IV after PMag treatment than untreated cells (Fig.…”