Apoptotic cells trigger the ABCA1/STAT6 pathway leading to PPAR- expression and activation in macrophages

Abstract

The signal transducer and activator of transcription 6 (STAT6) transcription factor activates peroxisome proliferator-activated receptor gamma (PPAR-)-regulated gene expression in immune cells. We investigated proximal membrane signaling that was initiated in macrophages after exposure to apoptotic cells that led to enhanced PPAR- expression and activity, using specific siRNAs for ABCA1, STAT6, and PPAR-, or their antagonists. The interactions between mouse bone marrow-derived macrophages or RAW 264.7 cells and apoptotic Jurkat cells, but not viable cells, resulted in the induction of STAT6 phosphorylation as well as PPAR- expression and activation. Knockdown of ATP-binding cassette transporter A1 (ABCA1) after the transfection of macrophages with ABCA1-specific siRNAs reduced apoptotic cell-induced STAT6 phosphorylation as well as PPAR- mRNA and protein expression. ABCA1 knockdown also reduced apoptotic cell-induced liver X receptor (LXR-) mRNA and protein expression. Moreover, inhibition of STAT6 with specific siRNAs or the pharmacological inhibitor AS1517499AS reversed the induction of PPAR-, LXR-, and ABCA1 by apoptotic Jurkat cells. PPAR--specific siRNAs or the PPAR- antagonist GW9662 inhibited apoptotic cell-induced increases in LXR- and ABCA1 mRNA and protein levels. Thus, these results indicate that apoptotic cells trigger the ABCA1/STAT6 pathway, leading to the activation of the PPAR-/LXR-/ABCA1 pathway in macrophages. The ABCA1-STAT6 pathway initiated by apoptotic cells is reinforced via a PPAR pathway.