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

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-P-3 formation and regulate cell survival, migration, and division. Activity of the PI3K delta isoform is enhanced in human SLE patient PBLs. In this study, we analyzed the effect of inhibiting PI3K delta in MRL/lpr mice, a model of human SLE. We found that PI3K delta inhibition ameliorated lupus progression. Treatment of these mice with a PI3K delta inhibitor reduced the excessive numbers of CD4+ effector/memory cells and B cells. In addition, this treatment reduced serum TNF-alpha levels and the number of macrophages infiltrating the kidney. Expression of inactive PI3K delta, but not deletion of the other hematopoietic isoform PI3K gamma, 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 PI3K delta. The observations that p110 delta inhibitor prolonged mouse life span, reduced disease symptoms, and showed no obvious secondary effects indicates that PI3K delta is a promising target for SLE.