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Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12

Nature Immunology volume 6, pages 579–586 (2005)Cite this article

A Corrigendum to this article was published on 01 February 2009

This article has been updated

Abstract

DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signals downstream of DAP12, showed a phenotype identical to that of DAP12-deficient macrophages. DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes. These data suggest that one or more DAP12-pairing receptors negatively regulate signaling through TLRs.

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Figure 1: DAP12-deficient macrophages secrete increased amounts of cytokines after TLR stimulation.
Figure 2: DAP12-deficient macrophages produce more TNF after TLR stimulation.
Figure 3: Reintroduction of DAP12 reduces the TNF production by DAP12-deficient macrophages in an ITAM-dependent manner.
Figure 4: Syk-deficient macrophages secrete increased amounts of proinflammatory cytokines in response to TLR stimulation.
Figure 5: Soluble inhibitory factor production does not explain differences between wild-type and DAP12-deficient macrophages.
Figure 6: LPS-induced ERK phosphorylation is increased in DAP12-deficient macrophages.
Figure 7: DAP12-deficient mice are more susceptible to endotoxic shock than wild-type mice.
Figure 8: DAP12-deficient mice have an enhanced innate immune response to infection with L. monocytogenes.

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  • 16 January 2009

    NOTE: In the version of this article initially published, the dose of D-galactosamine for the endotoxic shock experiments described in the Methods section (20 μg) was incorrect. The correct dose is 20 mg. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M.B. Humphrey for the DAP12 ITAM mutant construct and helpful discussions; Y. Hu for help with the generation of Syk-deficient chimeras; S. Watson for assistance in endotoxic shock experiments; C. Chu for help with dendritic cell cultures; T. Nishiya and D. Underhill for helpful discussions; and A. DeFranco for reading the manuscript. This work was supported by a grant from the Irvington Institute for Immunological Research (J.A.H.) and NIH grants CA89294 (L.L.L.) and DK58066 (to C.A.L.). L.L.L. is an American Cancer Society Research Professor and C.A.L. is a scholar of the Leukemia and Lymphoma Society.

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Authors and Affiliations

  1. Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, San Francisco, 94143, California, USA

    Jessica A Hamerman, Nadia K Tchao & Lewis L Lanier

  2. Department of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, 94143, California, USA

    Nadia K Tchao

  3. Department of Laboratory Medicine, University of California San Francisco, San Francisco, 94143, California, USA

    Clifford A Lowell

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Correspondence to Lewis L Lanier.

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Supplementary information

Supplementary Fig. 1

DAP12-deficient macrophages produce more TNF and IL-6 in response to FcγRII/III crosslinking. (PDF 44 kb)

Supplementary Fig. 2

TLR stimulation of wild-type and DAP12-deficient dendritic cells. (PDF 50 kb)

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Hamerman, J., Tchao, N., Lowell, C. et al. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat Immunol 6, 579–586 (2005). https://doi.org/10.1038/ni1204

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