Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation
Mai-Lan N. Huynh, … , Valerie A. Fadok, Peter M. Henson
Mai-Lan N. Huynh, … , Valerie A. Fadok, Peter M. Henson
Published January 1, 2002
Citation Information: J Clin Invest. 2002;109(1):41-50. https://doi.org/10.1172/JCI11638.
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Article

Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation

Abstract

Ingestion of apoptotic cells in vitro by macrophages induces TGF-β1 secretion, resulting in an anti-inflammatory effect and suppression of proinflammatory mediators. Here, we show in vivo that direct instillation of apoptotic cells enhanced the resolution of acute inflammation. This enhancement appeared to require phosphatidylserine (PS) on the apoptotic cells and local induction of TGF-β1. Working with thioglycollate-stimulated peritonea or LPS-stimulated lungs, we examined the effect of apoptotic cell uptake on TGF-β1 induction. Viable or opsonized apoptotic human Jurkat T cells, or apoptotic PLB-985 cells, human monomyelocytes that do not express PS during apoptosis, failed to induce TGF-β1. PS liposomes, or PS directly transferred onto the PLB-985 surface membranes, restored the TGF-β1 induction. Apoptotic cell instillation into LPS-stimulated lungs reduced proinflammatory chemokine levels in the bronchoalveolar lavage fluid (BALF). Additionally, total inflammatory cell counts in the BALF were markedly reduced 1–5 days after apoptotic cell instillation, an effect that could be reversed by opsonization or coinstillation of TGF-β1 neutralizing antibody. This reduction resulted from early decrease in neutrophils and later decreases in lymphocytes and macrophages. In conclusion, apoptotic cell recognition and clearance, via exposure of PS and ligation of its receptor, induce TGF-β1 secretion, resulting in accelerated resolution of inflammation.

Authors

Mai-Lan N. Huynh, Valerie A. Fadok, Peter M. Henson

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In vivo secretion of TGF-β1 in inflamed peritonea and lungs is increased...
In vivo secretion of TGF-β1 in inflamed peritonea and lungs is increased by apoptotic cell clearance. After intraperitoneal or endotracheal instillation of HBSS alone (control), viable Jurkat T cells (J), apoptotic Jurkat T cells (ApoJ), or opsonized apoptotic Jurkat T cells (OpApoJ) into LPS-stimulated lungs (2 days old) and thioglycollate-stimulated peritonea (3 days old), lavage supernatants collected after 4 hours and 1 hour, respectively, of incubation were assayed for TGF-β1 by ELISA. (a) ApoJ induced TGF-β1 when compared with control, while J and OpApoJ did not. (b) Phagocytic index (PI = number of apoptotic bodies/200 macrophages × 100) of peritoneal or bronchoalveolar lavage fluid cytospins showed low uptake in the control and J, and increased PI for both ApoJ and OpApoJ. (c) The TPMφ’s were isolated and cultured after in vivo instillation of cells; induction of TGF-β1 in the macrophages treated with apoptotic Jurkat T cells persisted for 18 and 36 hours in tissue culture, when compared with that in viable and opsonized apoptotic Jurkat T cells. (a) *P < 0.05, n = 6, ± SD; (b) *P < 0.05, n ≥ 12, ± SD; (c) *P < 0.05, n ≥ 10, ± SD.