Muropeptides trigger distinct activation profiles in macrophages and dendritic cells

Abstract

Bacterial peptidoglycan and its muropeptide derivatives potently activate mammalian innate immune system and are promising immunomodulators and vaccine adjuvants. However, their effects on human antigen-presenting cells, such as dendritic cells (DCs) and Mphi, are not fully understood. Lysozyme treatment of PG from Salmonella typhi yielded three muropeptides, GlcNAc–MurNAc–L-Ala–D-isoGlu– meso-DAP (GM-3P), GlcNAc–MurNAc–L-Ala–D-isoGlu– meso-DAP–D-Ala (GM-4P), and a dimer (GM-4P) 2, in which two GM-4P monomers are linked through their peptidic moieties. All three muropeptides induced TNF-α and IL-6 production by Mphi (GM-3P > GM-4P >> (GM-4P) 2), but failed to trigger TNF-α, IL-6 and IL-12p70 production by immature DCs. At the same time, muropeptide-stimulated DCs abundantly produced inflammatory chemokines IL-8, MIP-1α and MIP-1β, as well as displayed signs of phenotypic and functional maturation. Thus, muropeptide-dependent pro-inflammatory cytokine production is repressed in DCs. While this defect may be partly compensated in vivo by muropeptide-activated Mphi, neither Mphi nor DCs produce Th1- or Th17-polarizing cytokines upon muropeptide stimulation, which may contribute to the preferential induction of Th2 responses by muropeptides and should be taken into account when designing muropeptide-based immunomodulators and adjuvants.