WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs

Abstract

Clearance of invading pathogens is essential to preventing overwhelming inflammation and sepsis that are symptomatic of bacterial peritonitis. Macrophages participate in this innate immune response by engulfing and digesting pathogens, a process called phagocytosis. Oxidized phospholipids (OxPL) are dangerassociated molecular patterns (DAMPs) generated in response to infection that can prevent the phagocytic clearance of bacteria. We investigated the mechanism underlying OxPL action in macrophages. Exposure to OxPL induced alterations in actin polymerization, resulting in spreading of peritoneal macrophages and diminished uptake of E. coli. Pharmacological and cell-based studies showed that an anchored pool of PKA mediates the effects of OxPL. Gene silencing approaches identified the A-kinase anchoring protein (AKAP) WAVE1 as an effector of OxPL action in vitro. Chimeric Wave1 -/-mice survived significantly longer after infection with E. coli and OxPL treatment in vivo. Moreover, we found that endogenously generated OxPL in human peritoneal dialysis fluid from end-stage renal failure patients inhibited phagocytosis via WAVE1. Collectively, these data uncover an unanticipated role for WAVE1 as a critical modulator of the innate immune response to severe bacterial infections.

Exposure to Electronic Cigarettes Impairs Pulmonary Anti-Bacterial and Anti-Viral Defenses in a Mouse Model

“…The patient contained lipid-laden macrophages in the BAL, which the authors attributed to inhalation of glycerol-based E-cig vapor. Lipid-laden macrophages exhibit impaired bacterial phagocytosis [ 15 , 42 ]. Thus, it is likely that even E-cigs containing 0% nicotine will still alter the pulmonary response.…”

The effect of oxidized phospholipids on phenotypic polarization and function of macrophages

“…The Tabas group showed that OxPL induce apoptosis in macrophages undergoing ER-stress via CD36/TLR2 activation[68] and Gerhard Kronke’s group reported that 12/15 lipoxygenase plays a major and unexpected role in the non-inflammatory clearance of apoptotic cells, via a mechanism involving the formation of oxidized phosphatidylethanolamines (OxPE)[20]. On the other hand, phagocytosis was shown to be inhibited in macrophages by mm-LDL[69] and OxPAPC[58], and Sylvia Knapp’s group discovered that this inhibition involves WAVE1[70, 71], which is a cytoskeleton bound A-kinase anchoring protein. The group showed that WAVE1 knockout macrophages are resistant to OxPAPC-inhibited phagocytosis, and that the E. coli infected chimeric WAVE1-knockout mice have a better survival rate compared to controls[71].…”

“…On the other hand, phagocytosis was shown to be inhibited in macrophages by mm-LDL[69] and OxPAPC[58], and Sylvia Knapp’s group discovered that this inhibition involves WAVE1[70, 71], which is a cytoskeleton bound A-kinase anchoring protein. The group showed that WAVE1 knockout macrophages are resistant to OxPAPC-inhibited phagocytosis, and that the E. coli infected chimeric WAVE1-knockout mice have a better survival rate compared to controls[71]. Altogether, this has important implications in the regulation and outcome of inflammatory responses in atherosclerosis and sepsis.…”

Post-ischemic inflammation regulates neural damage and protection

“…Oxidized phospholipids are CD36 ligands that promote inflammation via TLR2 activation in ischemic brain ( Cho et al, 2005 ; Abe et al, 2010 ). The recognition and endocytosis of oxidized lipids by pattern recognition receptors could regulate post-ischemic inflammation ( Miller et al, 2011 ; Matt et al, 2013 ).…”