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J. Biol. Chem., Vol. 282, Issue 36, 26014-26025, September 7, 2007

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Acylation Determines the Toll-like receptor (TLR)-dependent Positive Versus TLR2-, Mannose Receptor-, and SIGNR1-independent Negative Regulation of Pro-inflammatory Cytokines by Mycobacterial Lipomannan^*

Emilie Doz, Stéphanie Rose, Jérôme Nigou, Martine Gilleron, Germain Puzo, François Erard, Bernhard Ryffel, and Valerie F. J. Quesniaux¹

From the Orleans University and CNRS, Molecular Immunology and Embryology, UMR6218, 45071 Orléans, France and Département des Mécanismes Moléculaires des Infections Mycobactériennes, Institut de Pharmacologie et de Biologie Structurale du CNRS, UMR5089, 31077 Toulouse, France

Mycobacterium tuberculosis lipomannans (LMs) modulate the host innate immune response. The total fraction of Mycobacterium bovis BCG LM was shown both to induce macrophage activation and pro-inflammatory cytokines through Toll-like receptor 2 (TLR2) and to inhibit pro-inflammatory cytokine production by lipopolysaccharide (LPS)-activated macrophages through a TLR2-independent pathway. The pro-inflammatory activity was attributed to tri- and tetra-acylated forms of BCG LM but not the mono- and di-acylated ones. Here, we further characterize the negative activities of M. bovis BCG LM on primary murine macrophage activation. We show that di-acylated LMs exhibit a potent inhibitory effect on cytokine and NO secretion by LPS-activated macrophages. The inhibitory activity of mycobacterial mannose-capped lipoarabino-mannans on human phagocytes was previously attributed to their binding to the C-type lectins mannose receptor or specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). However, we found that di-acylated LM inhibition of LPS-induced tumor necrosis factor secretion by murine macrophages was independent of TLR2, mannose receptor, or the murine ortholog SIGNR1. We further determined that tri-acyl-LM, an agonist of TLR2/TLR1, promoted interleukin-12 p40 and NO secretion through the adaptor proteins MyD88 and TIRAP, whereas the fraction containing tetra-acylated LM activated macrophages in a MyD88-dependent fashion, mostly through TLR4. TLR4-dependent pro-inflammatory activity was also seen with M. tuberculosis LM, composed mostly of tri-acylated LM, suggesting that acylation degree per se might not be sufficient to determine TLR2 versus TLR4 usage. Therefore, LM acylation pattern determines the anti-inflammatory versus pro-inflammatory effects of LM through different pattern recognition receptors or signaling pathways and may represent an additional mean of regulating the host innate immunity by mycobacteria.

Received for publication, March 29, 2007 , and in revised form, June 14, 2007.

^* This work was supported by a Franco-South African Research Cooperation Program grant (to V. F. Q.), by CNRS (to V. F. Q., B. R., J. N., M. G., and G. P.), and by ANR-05-MIIM-038-02 Grant TB-SIGN (to V. F. Q., B. R., J. N., M. G., and G. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: IEM UMR6218, CNRS, 3B rue de la Férollerie, 45071 Orléans Cedex2, France. Tel.: 33-238-255438; Fax: 33-238-257979; E-mail: quesniaux{at}cnrs-orleans.fr.

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