Wip1-dependent modulation of macrophage migration and phagocytosis

Abstract

Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis. Controlling macrophage conversion into foam cells remains a major challenge for treatment of atherosclerotic diseases. Here, we show that Wip1, a member of the PP2C family of Ser/Thr protein phosphatases, modulates macrophage migration and phagocytosis associated with atherosclerotic plaque formation. Wip1 deficiency increases migratory and phagocytic activities of the macrophage under stress conditions. Enhanced migration of Wip1-/- macrophages is mediated by Rac1-GTPase and PI3K/AKT signalling pathways. Elevated phagocytic ability of Wip1-/- macrophages is linked to CD36 plasma membrane recruitment that is regulated by AMPK activity. Our study identifies Wip1 as an intrinsic negative regulator of macrophage chemotaxis. We propose that Wip1-dependent control of macrophage function may provide avenues for preventing or eliminating plaque formation in atherosclerosis.

Protective role of melatonin in cardiac ischemia‐reperfusion injury: From pathogenesis to targeted therapy

“…Based on our clinical data, the fiber cap thickness of plaque is the independent predictor of cardiac IR injury. Statin drugs are proven to increase the fiber cap thickness and shift the lipid plaques to calcified ones, prompting plaque stability . Considering the anti‐inflammatory, antioxidant, and lipid regulatory action of melatonin, we have reason to believe that melatonin would reduce plaque vulnerability via modifying the fiber cap thickness and/or promoting plaque calcification.…”

Integrative Proteomic and Phosphoproteomic Profiling of Testis from Wip1 Phosphatase-Knockout Mice: Insights into Mechanisms of Reduced Fertility**

“…The gene encoding human Wip1, PPM1D, is highly expressed in testis (11). Wip1 phosphatase was originally studied as a potent regulator of tumorigenesis (12,13), and emerging evidence has indicated roles for Wip1 in multiple physiological processes and pathophysiological conditions, such as cellular homeostasis (14), neutrophil migration and inflammation (15), B-cell development (16), bone marrow mesenchymal stem cells and macrophage migration (17,18), autophagy, obesity, and atherosclerosis (19). Moreover, Wip1knockout (Wip1-KO) mice presented with defects of the male reproductive organs and impaired spermatogenesis, eventually leading to reduced fertility (11,20).…”

Syncytium calcium signaling and macrophage function in the heart

“…All these roles can be categorized into three biological processes: migration, endocytosis and phagocytosis. Cytoskeletal regulated migration drives cell movements in tissues and through endothelial cells to their final destinations, where they will carry out functions involved with Capg, Mpp1, Myo1f, Myo5a and Wip1 [ 4 , 27 – 29 ]. Endocytosis accomplished by macrophages is a receptor-mediated uptake process for liquids [ 30 ].…”

“…Phagocytosis as a first defense against pathogen attack is defined as the uptake for solid particles about a few micrometer in diameter. Phagocytosis involves recognition of endocytic receptors, vesicle trafficking and protein degradation, carbohydrate/lipid/DNA digestion and many other processes [ 4 , 31 – 33 ]. It is obvious that cell surface antigens are important for all three processes, whether for the cells to execute their tasks, or to distinguish which protocol to initiate.…”

“…Although macrophage functions in the immune system have been investigated extensively [ 1 – 3 ], the tissue-specific functions of macrophages in the heart are largely unknown. As the ATM/mTOR signaling, Rac1-GTPase, and PI3 K/AKT pathways play critical roles in controlling migration of cell [ 1 – 4 ], the multiple cell surface antigens such as CCR2/CD192, CD64/FcγR1, CX3CR1 and Mac3 were linked to origination of monocyte-macrophage differentiation and polarization in post myocardial infarction (MI) [ 5 – 9 ], but the molecular basis of macrophages migrating into specific tissues under physiological or pathological conditions, and fundamental knowledge of cell–cell recognition are much more obscure.…”