Abstract
BackgroundPulmonary exposure to high doses of engineered carbonaceous nanomaterials (NMs) is known to trigger inflammation in the lungs paralleled by an acute phase response. Toll-like receptors (TLRs), particularly TLR2 and TLR4, have recently been discussed as potential NM-sensors, initiating inflammation. Using Tlr2 and Tlr4 knock out (KO) mice, we addressed this hypothesis and compared the pattern of inflammation in lung and acute phase response in lung and liver 24 h after intratracheal instillation of three differently shaped carbonaceous NMs, spherical carbon black (CB), multi-walled carbon nanotubes (CNT), graphene oxide (GO) plates and bacterial lipopolysaccharide (LPS) as positive control.ResultsThe LPS control confirmed a distinct TLR4-dependency as well as a pronounced contribution of TLR2 by reducing the levels of pulmonary inflammation to 30 and 60% of levels in wild type (WT) mice. At the doses chosen, all NM caused comparable neutrophil influxes into the lungs of WT mice, and reduced levels were only detected for GO-exposed Tlr2 KO mice (35%) and for CNT-exposed Tlr4 KO mice (65%). LPS-induced gene expression was strongly TLR4-dependent. CB-induced gene expression was unaffected by TLR status. Both GO and MWCNT-induced Saa1 expression was TLR4-dependent. GO-induced expression of Cxcl2, Cxcl5, Saa1 and Saa3 were TLR2-dependent. NM-mediated hepatic acute phase response in terms of liver gene expression of Saa1 and Lcn2 was shown to depend on TLR2 for all three NMs. TLR4, in contrast, was only relevant for the acute phase response caused by CNTs, and as expected by LPS.ConclusionTLR2 and TLR4 signaling was not involved in the acute inflammatory response caused by CB exposure, but contributed considerably to that of GO and CNTs, respectively. The strong involvement of TLR2 in the hepatic acute phase response caused by pulmonary exposure to all three NMs deserves further investigations.
Highlights
Pulmonary exposure to high doses of engineered carbonaceous nanomaterials (NMs) is known to trigger inflammation in the lungs paralleled by an acute phase response
In conclusion, the involvement and requirement of TLR2 or TLR4 signaling for lung inflammation and lung and liver acute phase response differed between the three studied NMs, indicating that shape and surface chemistry may be determinants of the pathways triggered even at comparable levels of pulmonary inflammation
The graphene oxide (GO)-induced inflammation was to a considerable degree dependent on TLR2, and MWCNTinduced inflammation was partly TLR4-dependent
Summary
Pulmonary exposure to high doses of engineered carbonaceous nanomaterials (NMs) is known to trigger inflammation in the lungs paralleled by an acute phase response. Toll-like receptors (TLRs) belong to the family of PRRs and are activated upon binding with several ligands, often referred to as senses pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [7] initiating a signaling cascade leading to the release of cytokines and chemokines which recruits immune cells [8]. Carbonaceous NMs (C60, SWCNT and GO) were found to cause release of HMGB1 from mice lung cells, especially macrophages, leading to activation of the RAGE pathway (TLR pathway was not investigated) [15]. Acute phase response and the accompanying inflammatory response are strongly associated to increased risk of atherosclerosis [19, 20, 25]
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