Haptoglobin activates innate immunity to enhance acute transplant rejection in mice
Hua Shen, … , Margherita Maffei, Daniel R. Goldstein
Hua Shen, … , Margherita Maffei, Daniel R. Goldstein
Published December 12, 2011
Citation Information: J Clin Invest. 2012;122(1):383-387. https://doi.org/10.1172/JCI58344.
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Brief Report Transplantation

Haptoglobin activates innate immunity to enhance acute transplant rejection in mice

Abstract

Immune tolerance to transplanted organs is impaired when the innate immune system is activated in response to the tissue necrosis that occurs during harvesting and implantation procedures. A key molecule in this immune pathway is the intracellular TLR signal adaptor known as myeloid differentiation primary response gene 88 (MyD88). After transplantation, MyD88 induces DC maturation as well as the production of inflammatory mediators, such as IL-6 and TNF-α. However, upstream activators of MyD88 function in response to transplantation have not been identified. Here, we show that haptoglobin, an acute phase protein, is an initiator of this MyD88-dependent inflammatory process in a mouse model of skin transplantation. Necrotic lysates from transplanted skin elicited higher inflammatory responses in DCs than did nontransplanted lysates, suggesting DC-mediated responses are triggered by factors released during transplantation. Analysis of transplanted lysates identified haptoglobin as one of the proteins upregulated during transplantation. Expression of donor haptoglobin enhanced the onset of acute skin transplant rejection, whereas haptoglobin-deficient skin grafts showed delayed acute rejection and antidonor T cell priming in a MyD88-dependent graft rejection model. Thus, our results show that haptoglobin release following skin necrosis contributes to accelerated transplant rejection, with potential implications for the development of localized immunosuppressive therapies.

Authors

Hua Shen, Yang Song, Christopher M. Colangelo, Terence Wu, Can Bruce, Gaia Scabia, Anjela Galan, Margherita Maffei, Daniel R. Goldstein

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Figure 1

Lysates from nontransplanted necrotic skin induce MyD88-dependent production of IL-6 and TNF-α by DCs.

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Lysates from nontransplanted necrotic skin induce MyD88-dependent produc...
(A) Lysates from necrotic skin were cultured with DCs. IL-6 and TNF-α concentrations were determined using ELISA. Lysates alone did not contain cytokines (data not shown). (B) Lysates from necrotic skin or from necrotic cardiac tissue were cultured with DCs. and IL-6 was measured by ELISA. *P = 0.01, t test. (C and D) Necrotic skin lysates were cultured with WT, Myd88–/–, and Tlr2–/–Tlr4–/– DCs. IL-6 and TNF-α were determined using ELISA. P < 0.05 for Myd88–/– DCs versus WT or Tlr2–/–Tlr4–/– (t test). In the flow cytometric analysis, cells were gated on the CD11c+ pool, and expression of CD40 and CD86 was assessed after culture with control media or necrotic skin lysates. In A–D, results are representative of 1 experiment repeated independently 4 times with consistent results. Error bars represent SEM. Assays in each experiment run in triplicate.