PKA regulatory IIα subunit is essential for PGD2-mediated resolution of inflammation

Abstract

Activation of DP1 by PGD2 in macrophages induces the binding of PRKAR2A to the IFN-γR2 transmembrane region, inhibits JAK2/STAT1 signaling, and triggers the expression of antiinflammatory and reparative genes in myocardial infarction and sepsis.

Niacin Promotes Cardiac Healing after Myocardial Infarction through Activation of the Myeloid Prostaglandin D2 Receptor Subtype 1

“…We have also reported that DP1 mediates M2 polarization through suppression of the STAT1 pathway and activation of the STAT6 pathway (Kong et al, 2016). Similarly, here we found that niacin pretreatment depressed LPS/IFNg-induced STAT1 activation (Fig.…”

“…Consistent with this, H-PGDS deficiency results in impaired inflammatory resolution in mice (Rajakariar et al, 2007), and the proresolution effects of PGD 2 are believed to contribute to balancing the secretion of pro-versus antiinflammatory cytokines through the DP1 receptor (Rajakariar et al, 2007). We found that PGD 2 promotes M2 polarization and resolution of acute inflammation, including MI, through DP1-mediated suppression of JAK2-STAT1 signaling (Kong et al, 2016). Interestingly, in vascular inflammation animal models, DP1 activation restrains aneurysm formation in males and atherogenesis in females (Song et al, 2012).…”

“…We previously found that PGD 2 triggers macrophage M2 polarization (Kong et al, 2016). To explore whether niacin alters macrophage polarization through PGD 2 , we first tested PGD 2 generation in niacin-treated macrophages.…”

“…F/F mice were maintained on a C57BL/6 genetic background and crossed with C57BL/6 LysM Cre mice to generate DP1 F/F Lys Cre mice; these mice are referred to as macrophage (Mac)-DP1 knockout (KO) mice (Kong et al, 2016). DP1 F/F littermates [hereafter referred to as wild-type (WT) mice] were used as experimental controls.…”

“…Many studies have shown that cyclooxygenase-2-derived PGD 2 promotes resolution of inflammation (Rajakariar et al, 2007). DP1 is highly expressed in monocytes and macrophages (Rajakariar et al, 2007;Sandig et al, 2007), and PGD 2 -induced macrophage M2 polarization facilitates inflammatory resolution through DP1-mediated suppression of Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) 1 signaling (Kong et al, 2016). However, whether niacin shapes macrophage polarization and accelerates inflammatory resolution through PGD 2 release remains unclear.…”