Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice

Ait‐Oufella, Hafid; Kinugawa, Kiyoka; Zoll, Joffrey; Simon, Tabassome; Boddaert, Jacques; Heeneman, Silvia; Blanc‐Brude, Olivier; Barateau, Véronique; Potteaux, Stéphane; Merval, Régine; Esposito, Bruno; Teissier, Elisabeth; Daemen, Mat J.A.P.; Lesèche, Guy; Boulanger, Chantal M.; Tedgui, Alain; Mallat, Ziad

doi:10.1161/circulationaha.106.662080

Cited by 239 publications

(204 citation statements)

References 51 publications

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“…Mfge8 can regulate the differentiation of naive T cells into regulatory T cells (Tregs) and Th1 and Th17 cells (14)(15)(16). Each of these cell types has defined roles in asthma (17)(18)(19)(20).…”

Section: Resultsmentioning

confidence: 99%

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Kudo

Soltani

Sakuma

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8 −/− ) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8 −/− ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-α. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13-induced NF-κB activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.calcium sensitivity | lactadherin

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Section: Resultsmentioning

confidence: 99%

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Kudo

Soltani

Sakuma

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Tregs dampen the activity of effector T cells, and thus prevent excessive immune reactions, such as autoimmunity, but they can also prevent efficient immune responses, especially in the context of tumors. Two recent articles have proposed a regulatory T cell-promoting role for Mfge8/lactadherin in mice: in atherosclerosis (Ait-Oufella et al, 2007), or in granulocyte monocyte-colony stimulating factor-dependent induction of anti-tumor immune responses (Jinushi et al, 2007). More recently, the latter group has shown that subcutaneous grafts of mouse melanoma cells transfected with Mfge8 were infiltrated with Mfge8-expressing macrophages, regulatory T cells, and poorly efficient cytotoxic T cells when transplanted in mice (Jinushi et al, 2008), and thus became more aggressive.…”

Section: Discussionmentioning

confidence: 99%

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Sugano

Bernard‐Pierrot

et al. 2010

Oncogene

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Milk fat globule-epidermal growth factor-factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumorpromoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/ lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8.

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“…The MFG-E8 production from macrophages is increased by granulocyte/monocyte colony-stimulating factor (27,29) and fractalkine (CX 3 CL1) (30,31). Furthermore, it is reported that MFG-E8 expression, which is evaluated in human and animal models, is downregulated in some disease conditions such as autoimmune disease (14), Alzheimer disease (32), atherosclerosis (33), acute colitis (20), sepsis (10,31,(34)(35)(36) and I/R injury (37,38). However, in contrast, MFG-E8 is highly expressed in systemic lupus erythematosus (39), lung fibrosis (40), breast cancer (19) and melanoma (41).…”

Section: Mfg-e8 Structure and Productionmentioning

confidence: 99%

Milk Fat Globule-EGF Factor VIII in Sepsis and Ischemia-Reperfusion Injury

Matsuda

Jacob

et al. 2010

Mol Med

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Sepsis and ischemia-reperfusion (I/R) injury are among the leading causes of death in critically ill patients at the surgical intensive care unit setting. Both conditions are marked by the excessive inflammatory response which leads to a lethal disease complex such as acute lung injury, systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Despite the advances in the understanding of the pathophysiology of those conditions, very little progress has been made toward therapeutic interventions. One of the key aspects of these conditions is the accumulation of apoptotic cells that have the potential to release toxic and proinflammatory contents due to secondary necrosis without appropriate clearance by phagocytes. Along with the prevention of apoptosis, that is reported to be beneficial in sepsis and I/R injury, thwarting the development of secondary necrosis through the active removal of apoptotic cells via phagocytosis may offer a novel therapy. Milk fat globule-EGF factor VIII (MFG-E8), which is mainly produced by macrophages and dendritic cells, is an opsonin for apoptotic cells and acts as a bridging protein between apoptotic cells and phagocytes. Recently, we have shown that MFG-E8 expression is decreased in experimental sepsis and I/R injury models. Exogenous administration of MFG-E8 attenuated the inflammatory response as well as tissue injury and mortality through the promotion of phagocytosis of apoptotic cells. In this review, we describe novel information available about the involvement of MFG-E8 in the pathophysiology of sepsis and I/R injury, and the therapeutic potential of exogenous MFG-E8 treatment for those conditions.

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Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice

Cited by 239 publications

References 51 publications

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Milk Fat Globule-EGF Factor VIII in Sepsis and Ischemia-Reperfusion Injury

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