Formyl-Peptide Receptor Agonists and Amorphous SiO₂-NPs Synergistically and Selectively Increase the Inflammatory Responses of Human Monocytes and PMNs

Abstract

We tested whether amorphous SiO2-NPs and formylpeptide receptor (FPRs) agonists synergistically activate human monocytes and neutrophil polymorphonuclear granulocytes (PMNs). Peptide ligands specifically binding to FPR1 (f-MLP) and to FPR2 (MMK-1, WKYMVM and WKYMVm) human isoforms did not modify the association of SiO2-NPs to both cell types or their cytotoxic effects. Similarly, the extent of CD80, CD86, CD83, ICAM-1 and MHCII expression in monocytes treated with SiO2-NPs was not significantly altered by any FPRs agonist. However, FPR1 stimulation with f-MLP strongly increased the secretion of IL-1β, IL-6 and IL-8 by human monocytes, and of IL-8 by PMNs in the presence of SiO2-NPs, due to the synergic stimulation of gene transcription. FPR2 agonists also up-modulated the production of IL-1β induced by monocytes treated with SiO2-NPs. In turn, SiO2-NPs increased the chemotaxis of PMNs toward FPR1-specific ligands, but not toward FPR2-specific ones. Conversely, the chemotaxis of monocytes toward FPR2-specific peptides was inhibited by SiO2-NPs. NADPH-oxidase activation triggered by FPR1- and FPR2-specific ligands in both cell types was not altered by SiO2-NPs. Microbial and tissue danger signals sensed by FPRs selectively amplified the functional responses of monocytes and PMNS to SiO2-NPs, and should be carefully considered in the assessment of the risk associated with nanoparticle exposure.

Combined Action of Human Commensal Bacteria and Amorphous Silica Nanoparticles on the Viability and Immune Responses of Dendritic Cells

“…In fact, formyl peptide receptor agonists have been shown to synergize cytokine production by monocytes and the chemotactic response in PMNGs in the presence of SiO 2 NPs. However, no upregulation of maturation markers like that which was shown to occur in DCs was induced in these cells (39). No data on the possible up-modulation of costimulatory markers in macrophages under the conditions used in this study are currently available.…”

“…Such a possibility is indeed suggested by the little evidence that is available: endocytosed NPs and the lipopolysaccharide (LPS) of Gram-negative bacteria synergistically increase the levels of cytokine production by monocytes, macrophages, and DCs (17,(31)(32)(33)(34)(35)(36) and cytotoxicity in A549 epithelial cells (37). In addition, prokaryotic agonists of formyl peptide receptors (FPRs) synergize with different NP types [SiO 2 NPs, bare or pegylated organically modified silica NPs, poly(lactic-coglycolic acid) NPs, and liposomes] in determining specific inflammatory responses in monocytes and PMNs (38,39).…”

Bacteriocin BacSp222 and Its Succinylated Forms Exhibit Proinflammatory Activities Toward Innate Immune Cells

“… 59 The increased IL-8 expression is induced primarily via activation of PAMP receptors such as TLRs and FPRs. 36 , 60 However, cytokines and other molecules associated with inflammation are also potent stimulators of IL-8 expression. 61 , 62 The production of cytokines by immune cells exposed to bacteriocins is poorly understood; the published reports are mostly focused on nisin, but some of them are contradictory.…”

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

“…MMK-1, an FPR2 agonist, is by far the more commonly used peptide, and studies have shown that it may be useful as an anti-anxiety drug, as well as a drug to counteract hair loss from chemotherapy [98,104]. However, there has been some concern about its use in certain drug regimens, as it may amplify the response of monocytes to SIO 2 -coated nanoparticles, making it an important player in calculating the proper dosing when using such nanoparticles [105]. MMWLL is another M-peptide specific for FPR1.…”