title: NOD-like receptors and RIG-I-like receptors in human eosinophils: activation by NOD1 and NOD2 agonists.
abstract: NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) are newly discovered pattern-recognition receptors. They detect substructures of bacterial peptidoglycan and viral RNA, respectively, thereby initiating an immune response. However, their role in eosinophil activation remains to be explored. The aim of this study was to characterize the expression of a range of NLRs and RLRs in purified human eosinophils and assess their functional importance. Expression of NOD1, NOD2, NLRP3, RIG-I and MDA-5 was investigated using real-time reverse transcription PCR, flow cytometry and immunohistochemistry. The effects of the corresponding agonists iE-DAP (NOD1), MDP (NOD2), alum (NLRP3) and poly(I:C)/LyoVec (RIG-I/MDA-5) were studied in terms of cytokine secretion, degranulation, survival, expression of adhesion molecules and activation markers, and chemotactic migration. Eosinophils expressed NOD1 and NOD2 mRNA and protein. Low levels of RIG-I and MDA-5 were found, whereas expression of NLRP3 was completely absent. In accordance, stimulation with iE-DAP and MDP was found to induce secretion of interleukin-8, up-regulate expression of CD11b, conversely down-regulate CD62 ligand, increase expression of CD69 and induce migration. The MDP also promoted release of eosinophil-derived neurotoxin, whereas iE-DAP failed to do so. No effects were seen upon stimulation with alum or poly(I:C)/LyoVec. Moreover, the NOD1-induced and NOD2-induced activation was mediated via the nuclear factor-κB signalling pathway and augmented by interleukin-5 and granulocyte-macrophage colony-stimulating factor, but not interferon-γ. Taken together, the NLR system represents a novel pathway for eosinophil activation. The responses are enhanced in the presence of cytokines that regulate T helper type 2 immunity, suggesting that the NLRs constitute a link between respiratory infections and exacerbations of allergic disease.
authors: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. anne.mansson@ki.se
authors: Anne Månsson
authors: AM
authors: Kvarnhammar
authors: Terese
authors: T
authors: Petterson
authors: Lars-Olaf
authors: LO
authors: Cardell
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D047208:Eosinophil-Derived Neurotoxin / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D000072640:Interferon-Induced Helicase, IFIH1; D016209:Interleukin-8 / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000099192:CD69 Antigens
chemical_list: D000119:Acetylmuramyl-Alanyl-Isoglutamine; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D039481:CD11b Antigen; D002352:Carrier Proteins; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D003960:Diaminopimelic Acid; D047208:Eosinophil-Derived Neurotoxin; D000072640:Interferon-Induced Helicase, IFIH1; D016209:Interleukin-8; D019041:L-Selectin; D037181:Lectins, C-Type; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011971:Receptors, Immunologic; D000099192:CD69 Antigens; C453881:NLRP3 protein, human; C119067:NOD1 protein, human; C429018:NOD2 protein, human; C034331:N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid; C452820:RIGI protein, human; C452815:IFIH1 protein, human