Clearance of dying cells and autoimmunity

Michlewska, Sylwia; McColl, Aisleen; Rossi, Adriano G.; Megson, Ian L.; Dransfield, Ian

doi:10.1080/08916930701357208

Cited by 38 publications

(33 citation statements)

References 93 publications

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“…The onset of autoimmune-like syndromes [2]. Not only the phagocytic capacity, but the appearance of the 233 macrophages from this subline has also dramatically changed.…”

mentioning

confidence: 99%

Over-expression of integrin β3 can partially overcome the defect of integrin β3 signaling in transglutaminase 2 null macrophages

et al. 2009

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Macrophages 22 Apoptotic cells 23Transglutaminase 2 24Integrin signaling 25 a b s t r a c t Transglutaminase 2 (TG2) is a protein crosslinking enzyme with many additional biological functions. We have previously shown that in TG2 −/− mice the in vivo clearance of apoptotic cells is defective leading to autoimmunity. TG2 contributes to the formation of phagocytic portals by binding to both integrin ␤ 3 , a known phagocytic receptor, and its bridging molecule, MFG-E8. In TG2 null macrophages integrin ␤ 3 cannot accumulate around the apoptotic cells and its signaling is impaired. In the present study we describe a subline of TG2 null mice, in which a compensatory increase in integrin ␤ 3 expression, which resulted alone in a high receptor concentration around the apoptotic cells without the requirement for accumulation, partially corrected the defect in integrin ␤ 3 signaling. Our data provide a proof for the concept that the function of TG2 is to stabilize accumulated integrin ␤ 3 concentration in the phagocytic cup.

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“…The onset of autoimmune-like syndromes [2]. Not only the phagocytic capacity, but the appearance of the 233 macrophages from this subline has also dramatically changed.…”

mentioning

confidence: 99%

Over-expression of integrin β3 can partially overcome the defect of integrin β3 signaling in transglutaminase 2 null macrophages

et al. 2009

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“…2,3 The coordinated timeliness and effectiveness of the cell 'waste' disposal is crucial for the maintenance of immune tolerance and tissue homeostasis. 4,5 It is now well accepted that the anionic phospholipid, phosphatidylserine (PS) -normally confined to the inner leaflet of the plasma membrane -serves as a universal 'eat-me' signal when externalized to the surface of dying cells. 6 Paradoxically, however, phagocytes are known to express multiple types of receptors for clearance of dead cells raising the question about the purpose for this apparent redundancy.…”

mentioning

confidence: 99%

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

et al. 2014

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Diversified anionic phospholipids, phosphatidylserines (PS), externalized to the surface of apoptotic cells are universal phagocytic signals. However, the role of major PS metabolites, such as peroxidized species of PS (PSox) and lyso-PS, in the clearance of apoptotic cells has not been rigorously evaluated. Here, we demonstrate that H 2 O 2 was equally effective in inducing apoptosis and externalization of PS in naive HL60 cells and in cells enriched with oxidizable polyunsaturated species of PS (supplemented with linoleic acid (LA)). Despite this, the uptake of LA-supplemented cells by RAW264.7 and THP-1 macrophages was more than an order of magnitude more effective than that of naive cells. A similar stimulation of phagocytosis was observed with LA-enriched HL60 cells and Jurkat cells triggered to apoptosis with staurosporine. This was due to the presence of PSox on the surface of apoptotic LA-supplemented cells (but not of naive cells). This enhanced phagocytosis was dependent on activation of the intrinsic apoptotic pathway, as no stimulation of phagocytosis occurred in LA-enriched cells challenged with Fas antibody. Incubation of apoptotic cells with lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), a secreted enzyme with high specificity towards PSox, hydrolyzed peroxidized PS species in LA-supplemented cells resulting in the suppression of phagocytosis to the levels observed for naive cells. This suppression of phagocytosis by Lp-PLA 2 was blocked by a selective inhibitor of Lp-PLA 2 , SB-435495. Screening of possible receptor candidates revealed the ability of several PS receptors and bridging proteins to recognize both PS and PSox, albeit with diverse selectivity. We conclude that PSox is an effective phagocytic 'eat-me' signal that participates in the engulfment of cells undergoing intrinsic apoptosis.

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“…The culmination of the apoptotic program is the phagocytosis of the apoptotic cell. In mammals prompt removal of apoptotic cells is required to prevent the release of potential self-Ags and the onset of autoimmune-like syndromes (2).…”

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confidence: 99%

Transglutaminase 2 Is Needed for the Formation of an Efficient Phagocyte Portal in Macrophages Engulfing Apoptotic Cells

Tóth

Garabuczi

Sarang

et al. 2009

The Journal of Immunology

129

159

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Transglutaminase 2 (TG2), a protein cross-linking enzyme with many additional biological functions, acts as coreceptor for integrin β3. We have previously shown that TG2−/− mice develop an age-dependent autoimmunity due to defective in vivo clearance of apoptotic cells. Here we report that TG2 on the cell surface and in guanine nucleotide-bound form promotes phagocytosis. Besides being a binding partner for integrin β3, a receptor known to mediate the uptake of apoptotic cells via activating Rac1, we also show that TG2 binds MFG-E8 (milk fat globulin EGF factor 8), a protein known to bridge integrin β3 to apoptotic cells. Finally, we report that in wild-type macrophages one or two engulfing portals are formed during phagocytosis of apoptotic cells that are characterized by accumulation of integrin β3 and Rac1. In the absence of TG2, integrin β3 cannot properly recognize the apoptotic cells, is not accumulated in the phagocytic cup, and its signaling is impaired. As a result, the formation of the engulfing portals, as well as the portals formed, is much less efficient. We propose that TG2 has a novel function to stabilize efficient phagocytic portals.

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Clearance of dying cells and autoimmunity

Cited by 38 publications

References 93 publications

Over-expression of integrin β3 can partially overcome the defect of integrin β3 signaling in transglutaminase 2 null macrophages

Over-expression of integrin β3 can partially overcome the defect of integrin β3 signaling in transglutaminase 2 null macrophages

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

Transglutaminase 2 Is Needed for the Formation of an Efficient Phagocyte Portal in Macrophages Engulfing Apoptotic Cells

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