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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.

More information

Type
Journal Article
Author
Schenk M
Krutzik SR
Sieling PA
Lee DJ
Teles RM B
Ochoa MT
Komisopoulou E
Sarno EN
Rea TH
Graeber TG
Kim S
Cheng G
Modlin RL
Country
USA
Year of Publication
2012
Journal
Nature medicine
Volume
18
Issue
4
Number of Pages
555-63
Date Published
2012 Mar 25
Language
eng
ISSN Number
1546-170X
DOI
10.1038/nm.2650
Alternate Journal
Nat. Med.
Publication Language
eng