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MyD88-Dependent and MyD88-Independent Pathways in Synergy, Priming, and Tolerance between TLR Agonists¹

Aranya Bagchi^*, Elizabeth A. Herrup^*, H. Shaw Warren, James Trigilio^*, Hae-Sook Shin^*, Catherine Valentine and Judith Hellman^2,

^* Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA 02114; Department of Pediatrics, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, and Infectious Disease Unit, Massachusetts General Hospital, Charlestown, MA 02129; Department of Medicine, and Infectious Disease Unit, Massachusetts General Hospital, Charlestown, MA 02129; and Department of Anesthesia and Critical Care, Massachusetts General Hospital, Department of Anesthesia, Harvard Medical School, and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Charlestown, MA 02129

TLRs sense components of microorganisms and are critical host mediators of inflammation during infection. Different TLR agonists can profoundly alter inflammatory effects of one another, and studies suggest that the sequence of exposure to TLR agonists may importantly impact on responses during infection. We tested the hypothesis that synergy, priming, and tolerance between TLR agonists follow a pattern that can be predicted based on differential engagement of the MyD88-dependent (D) and the MyD88-independent (I) intracellular signaling pathways. Inflammatory effects of combinations of D and I pathway agonists were quantified in vivo and in vitro. Experiments used several D-specific agonists, an I-specific agonist (poly(I:C)), and LPS, which acts through both the D and I pathways. D-specific agonists included: peptidoglycan-associated lipoprotein, Pam3Cys, flagellin, and CpG DNA, which act through TLR2 (peptidoglycan-associated lipoprotein and Pam3Cys), TLR5, and TLR9, respectively. D and I agonists were markedly synergistic in inducing cytokine production in vivo in mice. All of the D-specific agonists were synergistic with poly(I:C) in vitro in inducing TNF and IL-6 production by mouse bone marrow-derived macrophages. Pretreatment of bone marrow-derived macrophages with poly(I:C) led to a primed response to subsequent D-specific agonists and vice versa, as indicated by increased cytokine production, and increased NF-B translocation. Pretreatment with a D-specific agonist augmented LPS-induced IFN- production. All D-specific agonists induced tolerance to one another. Thus, under the conditions studied here, simultaneous and sequential activation of both the D and I pathways causes synergy and priming, respectively, and tolerance is induced by agonists that act through the same pathway.

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 This work was funded by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (Grants K08-AI01722, R01 AI058106, and R01-GM59694).

² Address correspondence and reprint requests to Dr. Judith Hellman, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail address: jhellman{at}partners.org

³ Abbreviations used in this paper: PAL, peptidoglycan-associated lipoprotein; BMDM, bone marrow-derived macrophage; D, MyD88 dependent; I, MyD88 independent; KO, knockout.

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