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Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels
David J. Rowlands, … , Sunita Bhattacharya, Jahar Bhattacharya
David J. Rowlands, … , Sunita Bhattacharya, Jahar Bhattacharya
Published April 25, 2011
Citation Information: J Clin Invest. 2011;121(5):1986-1999. https://doi.org/10.1172/JCI43839.
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Research Article

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

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Abstract

Shedding of the extracellular domain of cytokine receptors allows the diffusion of soluble receptors into the extracellular space; these then bind and neutralize their cytokine ligands, thus dampening inflammatory responses. The molecular mechanisms that control this process, and the extent to which shedding regulates cytokine-induced microvascular inflammation, are not well defined. Here, we used real-time confocal microscopy of mouse lung microvascular endothelium to demonstrate that mitochondria are key regulators of this process. The proinflammatory cytokine soluble TNF-α (sTNF-α) increased mitochondrial Ca2+, and the purinergic receptor P2Y2 prolonged the response. Concomitantly, the proinflammatory receptor TNF-α receptor–1 (TNFR1) was shed from the endothelial surface. Inhibiting the mitochondrial Ca2+ increase blocked the shedding and augmented inflammation, as denoted by increases in endothelial expression of the leukocyte adhesion receptor E-selectin and in microvascular leukocyte recruitment. The shedding was also blocked in microvessels after knockdown of a complex III component and after mitochondria-targeted catalase overexpression. Endothelial deletion of the TNF-α converting enzyme (TACE) prevented the TNF-α receptor shedding response, which suggests that exposure of microvascular endothelium to sTNF-α induced a Ca2+-dependent increase of mitochondrial H2O2 that caused TNFR1 shedding through TACE activation. These findings provide what we believe to be the first evidence that endothelial mitochondria regulate TNFR1 shedding and thereby determine the severity of sTNF-α–induced microvascular inflammation.

Authors

David J. Rowlands, Mohammad Naimul Islam, Shonit R. Das, Alice Huertas, Sadiqa K. Quadri, Keisuke Horiuchi, Nilufar Inamdar, Memet T. Emin, Jens Lindert, Vadim S. Ten, Sunita Bhattacharya, Jahar Bhattacharya

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Figure 1

Lung microvessels shed TNFR1 ectodomains.

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Lung microvessels shed TNFR1 ectodomains.
(A) Confocal images showing en...
(A) Confocal images showing endothelial fluorescence in microvessels infused with calcein (5 μM, 20 minutes) or the anti-TNFR1 mAb MCA2350 (40 μg/ml, 5 minutes). Images were obtained 30 minutes after infusion with buffer or 0.01% TB. The image at right was obtained from a separate vessel 30 minutes after labeling for TNFR1. Alv, alveolus; Lum, microvascular lumen. Scale bar: 50 μm. (B and C) Endothelial TNFR1 fluorescence in microvessels infused with buffer control or sTNF-α (1 ng/ml) for 10 minutes. Scale bar: 25 μm. (D) Line-scan analyses of endothelial immunofluorescence in vessels given buffer control, goat IgG, sTNF-α, or sTNF-α in the presence of TNFR1 blocking mAb E20 (40 μg/ml). n = 4 per group per time point. *P < 0.05 versus control. (E and F) Effects of TACE (E) and LPS (F) on sTNF-α–induced TNFR1 shedding in microvessels. Data were obtained 1 hour after intratracheal instillation. TAP, TAPI-1 (50 μM); LPS (1 mg/kg). *P < 0.05 versus control; #P < 0.05 versus sTNF-α. (G) IB of lysates of lung tissue (replicated 3 times). (H and I) TNFR1 surface expression in primary isolates of ECs (red boxes denote vWF-positive cells) derived from lungs treated as indicated.

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