Mannodendrimers prevent acute lung inflammation by inhibiting neutrophil recruitment

被引：98

作者：

Blattes, Emilyne ^{[1
,2
]}

Vercellone, Alain ^{[1
,2
]}

Eutamene, Helene ^{[3
,4
]}

Turrin, Cedric-Olivier ^{[5
,6
]}

Theodorou, Vassilia ^{[3
,4
]}

Majoral, Jean-Pierre ^{[5
,6
]}

Caminade, Anne-Marie ^{[5
,6
]}

Prandi, Jacques ^{[1
,2
]}

Nigou, Jerome ^{[1
,2
]}

Puzo, Germain ^{[1
,2
]}

机构：

[1] Inst Pharmacol & Biol Struct, Ctr Natl Rech Sci, F-31077 Toulouse, France

[2] Univ Paul Sabatier, Univ Toulouse, Inst Pharmacol & Biol Struct, F-31077 Toulouse, France

[3] INRA, Toxicol Alimentaire, F-31027 Toulouse, France

[4] Univ Paul Sabatier, Univ Toulouse, Inst Natl Polytech Toulouse, Toxicol Alimentaire, F-31027 Toulouse, France

[5] CNRS, Lab Chim Coordinat, F-31077 Toulouse, France

[6] Univ Paul Sabatier, Univ Toulouse, Inst Natl Polytech Toulouse, Lab Chim Coordinat, F-31077 Toulouse, France

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 22期

关键词：

antiinflammatory molecule; SIGNR1; targeting; glycodendrimer synthesis; multivalent ligands; ManLAM functional analogs; PHOSPHORUS-CONTAINING DENDRIMERS; LECTIN DC-SIGN; MYCOBACTERIAL LIPOARABINOMANNANS; SELECTIVE RECOGNITION; ORGANIZATION; BINDING; CELLS;

D O I：

10.1073/pnas.1221708110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (alpha 1 -> 2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-alpha, production by LPS-stimulated DCs in a DC-SIGN-dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases.

引用

页码：8795 / 8800

页数：6

共 32 条

[1] Endothelium-derived toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs [J].