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NOD2 triggers an interleukin-32–dependent human dendritic cell program in leprosy

Abstract

It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony–stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I–restricted CD8+ T cells. Expression of NOD2 and IL-32 and the frequency of CD1b+ DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand–induced, IL-32–dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.

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Figure 1: NOD2L and TLR2/1L induce functionally divergent DC-specific pathways.
Figure 2: NOD2L is a potent inducer of functional CD1b+ DCs.
Figure 3: NOD2L induces an IL-32–dependent DC program.
Figure 4: IL-32–induced DCs are potent antigen-presenting cells for MHC class I–restricted antigens.
Figure 5: IL-32 activates a DC program in leprosy.
Figure 6: Monocytes from patients with L-lep show reduced induction of CD1b+ DCs in response to NOD2L compared to healthy controls.

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Acknowledgements

We thank P. Liu, B. Bloom and F. Martinon for helpful scientific discussions, D. Vu for technical assistance and A. De Leon for help with the immunolabeling. This work was supported in parts by grants from the US National Institutes of Health (R01s AI022553, AR040312 and AI047868) and the Swiss National Science Foundation (SSMBS, PASMP3-123256).

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Contributions

R.L.M. and M.S. designed the experiments, interpreted the data and did the majority of the writing. M.S., S.R.K. and P.A.S. performed the experiments. D.J.L. helped with functional microarray analysis. R.M.B.T. provided the leprosy microarray data. M.T.O. performed the confocal imaging. E.K. and T.G.G. performed the bioinformatics analysis. E.N.S. and T.H.R. provided the clinical samples and helped interpret data. S.K. provided reagents and expertise on IL-32. G.C. helped with the conceptual framework and direction of the study.

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Correspondence to Robert L Modlin.

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The authors declare no competing financial interests.

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Schenk, M., Krutzik, S., Sieling, P. et al. NOD2 triggers an interleukin-32–dependent human dendritic cell program in leprosy. Nat Med 18, 555–563 (2012). https://doi.org/10.1038/nm.2650

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