Milk fat globule–EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium

Bu, Heng Fu; Zuo, Xiu Li; Wang, Xiao; Ensslin, Michael A.; Koti, Vjola; Hsueh, Wei; Raymond, Adam; Shur, Barry D.; Tan, Xiao Di

doi:10.1172/jci31841

Cited by 149 publications

(218 citation statements)

References 37 publications

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“…The functional roles of MFG-E8-associated tissue remodeling have been investigated widely, they include promoting removal of apoptotic lymphocytes by macrophages (13,14), clearance of mammary epithelial cells in involution (12), mediating sperm-egg bindings (11), maintenance of intestinal epithelium (10) and facilitating neovascularization as a downstream effector of vascular endothelial growth factor (VEGF) signaling (15). The MFG-E8 production from macrophages is increased by granulocyte/monocyte colony-stimulating factor (27,29) and fractalkine (CX 3 CL1) (30,31).…”

Section: Mfg-e8 Structure and Productionmentioning

confidence: 99%

“…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%

“…Previous investigators have shown that MFG-E8 participates in multi-ple physiological processes associated with tissue remodeling (10)(11)(12)(13)(14)(15). Among these, its role for the clearance of apoptotic cells has made a huge impact on subsequent research.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Mfg-e8 Structure and Productionmentioning

confidence: 99%

Section: Mfg-e8 Structure and Productionmentioning

confidence: 99%

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

Matsuda

Jacob

et al. 2010

Mol Med

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“…Second, on endothelial cells, MFGE8/lactadherin binding to avb3/b5 integrins promotes vascular endothelial growth factor (VEGF)-induced survival and proliferation, leading to angiogenesis (Silvestre et al, 2005). Third, MFGE8 promotes cell/cell and cell/extracellular matrix (ECM) adhesion, through an unknown ligand, during sperm-oocyte interaction (Ensslin and Shur, 2003), and physiologic migration of epithelial cells in intestine (Bu et al, 2007) and mammary gland (Ensslin and Shur, 2007).…”

Section: Introductionmentioning

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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“…For all assays, viable cells were purified by Ficoll (GE Life Sciences) gradient centrifugation before culturing with the indicated drug. Cells were cultured for 18 h with the indicated treatments, and apoptosis was evaluated by measuring phosphatidylserine exposure using A647-labeled MFG-E8 binding (56) and permeability using 7-AAD (Biolegend) or the viability dye eFluor 506 (eBiosciences). For all dose-response curves depicting cell killing by drugs, the death shown is the death measured above baseline (untreated cells), which was typically 10-15%.…”

Section: Methodsmentioning

confidence: 99%

Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases

McNally

Millen

Chaturvedi

et al. 2017

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

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Antigen-activated lymphocytes undergo extraordinarily rapid cell division in the course of immune responses. We hypothesized that this unique aspect of lymphocyte biology leads to unusual genomic stress in recently antigen-activated lymphocytes and that targeted manipulation of DNA damage-response (DDR) signaling pathways would allow for selective therapeutic targeting of pathological T cells in disease contexts. Consistent with these hypotheses, we found that activated mouse and human T cells display a pronounced DDR in vitro and in vivo. Upon screening a variety of small-molecule compounds, we found that potentiation of p53 (via inhibition of MDM2) or impairment of cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) led to the selective elimination of activated, pathological T cells in vivo. The combination of these strategies [which we termed "p53 potentiation with checkpoint abrogation" (PPCA)] displayed therapeutic benefits in preclinical disease models of hemophagocytic lymphohistiocytosis and multiple sclerosis, which are driven by foreign antigens or self-antigens, respectively. PPCA therapy targeted pathological T cells but did not compromise naive, regulatory, or quiescent memory T-cell pools, and had a modest nonimmune toxicity profile. Thus, PPCA is a therapeutic modality for selective, antigen-specific immune modulation with significant translational potential for diverse immune-mediated diseases.autoimmunity | immune regulation | DNA damage response | therapeutics T he immune system has evolved under intense pressure from pathogens that proliferate very rapidly (1). In responding to infections, the adaptive immune system needs to mobilize rare pathogen-specific lymphocytes quickly. This mobilization is achieved by rapid, exponential expansion of responding lymphocyte clones. Indeed, antigen-activated T and B cells appear to have some of the most rapid division rates among all mammalian cell types (2). We hypothesized that this unique aspect of lymphocyte biology would cause significant genomic stress in responding lymphocytes and that novel forms of therapeutic immune suppression could be developed by exploiting this weakness. Such strategies would allow for "developmental" or "kinetic" targeting of pathological immune responses at the time of disease activity or organ rejection and could complement or replace chronic suppression of immune signaling or cytokine pathways. The recent preclinical and clinical development of a wide array of rationally designed small-molecule inhibitors of various signaling and effector molecules within DNA damage-response (DDR) cascades has provided an opportunity to test this hypothesis (3, 4).We first looked for evidence of a DDR occurring in activated T cells in physiological contexts and found a broad DDR in murine and human T cells. Next, upon screening an array of DNA-damaging agents and DDR-altering small molecules for their ability to kill activated, but not resting, T cells, we identified two promising strategies. We found that inhibition of MDM2 (an end...

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Milk fat globule–EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium

Cited by 149 publications

References 37 publications

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

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

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

Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases

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