Kvarnhammar, AM; Petterson, T; Cardell, LO
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-kappa B signalling pathway and augmented by interleukin-5 and granulocyte-
macrophage colony-stimulating factor, but not interferon-gamma. 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.