Article

PDF
Access to the PDF text
Advertising


Free Article !

Archives of cardiovascular diseases
Volume 102, n° S1
pages 12-13 (mars 2009)
Doi : 10.1016/S1875-2136(09)72151-5
A018 Modulation of macrophage activation state protects tissue from necrosis during critical limb ischemia in thrombospondin-1-deficient mice
 

N. Brechot 1, E. Gomez 1, M. Bignon 1, J. Khallou-Laschet 2, M. Dussiot 2, A. Cazes 1, C. Alanio-Bréchot 3, M. Durand 1, J. Philippe 1, J.-S. Silvestre 4, N. Van Rooijen 5, P. Corvol 1, A. Nicoletti 2, B. Chazaud 6, S. Germain 1, 6
1 Inserm U833 – College de France, Paris, France 
2 Inserm U872, Paris, France 
3 Laboratoire d’Hématologie, Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre, France 
4 Inserm U567, Paris, France 
5 Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, Amsterdam, The Netherlands 
6 Service d’Hématologie Biologique A, HEGP, AP-HP, Paris, France 

@@#100979@@
Background

Macrophages, key regulators of healing/regeneration processes, strongly infiltrate ischemic tissues from patients suffering from critical limb ischemia (CLI). However pro-inflammatory markers correlate with disease progression and risk of amputation, suggesting that modulating macrophage activation state might be beneficial. We previously reported that thrombospondin-1 (TSP-1) is highly expressed in ischemic tissues during CLI in humans. TSP-1 is a matricellular protein that displays well-known angiostatic properties in cancer, and regulates inflammation in vivo and macrophages properties in vitro. We therefore sought to investigate its function in a mouse model of CLI.

Methods and findings

Using a genetic model of tsp-1-/- mice subjected to femoral artery excision, we report that tsp-1-/- mice were clinically and histologically protected from necrosis compared to controls. Tissue protection was associated with increased postischemic angiogenesis and muscle regeneration. We next showed that macrophages present in ischemic tissues exhibited distinct phenotypes in tsp-1-/- and wt mice. A strong reduction of necrotic myofibers phagocytosis was observed in tsp-1-/- mice. We next demonstrated that phagocytosis of muscle cell debris is a potent pro-inflammatory signal for macrophages in vitro. Consistently with these findings, macrophages that infiltrated ischemic tissues exhibited a reduced postischemic pro-inflammatory activation state in tsp-1-/- mice, characterized by a reduced Ly-6C expression and a less pro-inflammatory cytokine expression profile. Finally, we showed that monocyte depletion reversed clinical and histological protection from necrosis observed in tsp-1-/- mice, thereby demonstrating that macrophages mediated tissue protection in these mice.

Conclusion

This study defines targeting postischemic macrophage activation state as a new potential therapeutic approach to protect tissues from necrosis and promote tissue repair during CLI. Furthermore, our data suggest that phagocytosis plays a crucial role in promoting a deleterious intra-tissular pro-inflammatory macrophage activation state during critical injuries. Finally, our results describe TSP-1 as a new relevant physiological target during critical leg ischemia.

The full text of this article is available in PDF format.
The full text of this article is available in PDF format.
Click here to see it.


© 2009  Elsevier Masson SAS. All Rights Reserved.
EM-CONSULTE.COM is registrered at the CNIL, déclaration n° 1286925.
As per the Law relating to information storage and personal integrity, you have the right to oppose (art 26 of that law), access (art 34 of that law) and rectify (art 36 of that law) your personal data. You may thus request that your data, should it be inaccurate, incomplete, unclear, outdated, not be used or stored, be corrected, clarified, updated or deleted.
Personal information regarding our website's visitors, including their identity, is confidential.
The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
Close
Article Outline
You can move this window by clicking on the headline
@@#110903@@