title: 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.
authors.affiliation: Department of Medicine, Division of Dermatology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California, USA.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schenk
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Krutzik
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sieling
authors.forename: Delphine J
authors.initials: DJ
authors.lastname: Lee
authors.forename: Rosane M B
authors.initials: RM
authors.lastname: Teles
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ochoa
authors.forename: Evangelia
authors.initials: E
authors.lastname: Komisopoulou
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rea
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Soohyun
authors.initials: S
authors.lastname: Kim
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D015703:Antigens, CD; D039481:CD11b Antigen; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D007918:Leprosy / Q000473:pathology*; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D039481:CD11b Antigen; D016207:Cytokines; C496971:IL32 protein, human; D007378:Interleukins; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor