TiO2 nanoparticles (NPs) are extensively used in various applications, highlighting the importance of ongoing research into their effects. This work belongs among rare whole-body inhalation studies investigating the effects of TiO2 NPs on mice. Unlike previous studies, the concentration of TiO2 NPs in the inhalation chamber (130.8 μg/m3) was significantly lower. This 11-week study on mice confirmed in vivo the presence of TiO2 NPs in lung macrophages and type II pneumocytes including their intracellular localization by using the electron microscopy and the state-of-the-art methods detecting NPs' chemical identity/crystal structure, such as the energy-dispersed X-ray spectroscopy (EDX), cathodoluminescence (CL), and detailed diffraction pattern analysis using powder nanobeam diffraction (PNBD). For the first time in inhalation study in vivo, the alterations in erythrocyte morphology with evidence of echinocytes and stomatocytes, accompanied by iron accumulation in spleen, liver, and kidney, are reported following NP's exposure. Together with the histopathological evidence of hyperaemia in the spleen and kidney, and haemosiderin presence in the spleen, the finding of NPs containing iron might suggest the increased decomposition of damaged erythrocytes. The detection of TiO2 NPs on erythrocytes through CL analysis confirmed their potential systemic availability. On the contrary, TiO2 NPs were not confirmed in other organs (spleen, liver, and kidney); Ti was detected only in the kidney near the detection limit.

• Klíčová slova
• cathodoluminescence, electron microscopy, lung, powder nanobeam diffraction, titanium dioxide nanoparticles,
• MeSH
• aplikace inhalační MeSH
• erytrocyty * účinky léků   patologie   MeSH
• inhalační expozice * škodlivé účinky   MeSH
• kovové nanočástice * toxicita   MeSH
• myši MeSH
• nanočástice * toxicita   MeSH
• plíce * účinky léků   metabolismus   patologie   MeSH
• testy subchronické toxicity MeSH
• titan * toxicita   farmakokinetika   aplikace a dávkování   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• titan * MeSH
• titanium dioxide MeSH Prohlížeč

INTRODUCTION: A critical step preceding the potential biomedical application of nanoparticles is the evaluation of their immunomodulatory effects. Such nanoparticles are expected to enter the bloodstream where they can be recognized and processed by circulating monocytes. Despite the required biocompatibility, this interaction can affect intracellular homeostasis and modulate physiological functions, particularly inflammation. This study focuses on titanium dioxide (TiO2) as an example of relatively low cytotoxic nanoparticles with potential biomedical use and aims to evaluate their possible modulatory effects on the inflammasome-based response in human primary monocytes. METHODS: Monocyte viability, phenotypic changes, and cytokine production were determined after exposure to TiO2 (diameter, 25 nm; P25) alone. In the case of the modulatory effects, we focused on NLRP3 activation. The production of IL-1β and IL-10 was evaluated after (a) simultaneous activation of monocytes with bacterial stimuli muramyl dipeptide (MDP), or lipopolysaccharide (LPS), and TiO2 (co-exposure model), (b) prior activation with TiO2 alone and subsequent exposure to bacterial stimuli MDP or LPS. The differentiation of TiO2-treated monocytes into macrophages and their polarization were also assessed. RESULTS: The selected TiO2 concentration range (30-120 µg/mL) did not induce any significant cytotoxic effects. The highest dose of TiO2 promoted monocyte survival and differentiation into macrophages, with the M2 subset being the most prevalent. Nanoparticles alone did not induce substantial production of inflammatory cytokines IL-1β, IL-6, or TNF-α. The immunomodulatory effect on NLRP3 depended on the type of costimulant used. While co-exposure of monocytes to MDP and TiO2 boosted NLRP3 activity, co-exposure to LPS and TiO2 inhibited NLRP3 by enhancing IL-10 release. The inhibitory effect of TiO2 on NLRP3 based on the promotion of IL-10 was confirmed in a post-exposure model for both costimulants. CONCLUSION: This study confirmed a non-negligible modulatory effect on primary monocytes in their inflammasome-based response and differentiation ability.

• Klíčová slova
• NLRP3, TiO2 nanoparticles, immunomodulation, macrophages, monocytes, polarization,
• MeSH
• acetylmuramyl-alanyl-isoglutamin farmakologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• cytokiny metabolismus   MeSH
• inflamasomy účinky léků   imunologie   metabolismus   MeSH
• interleukin-10 metabolismus   MeSH
• interleukin-1beta metabolismus   MeSH
• kovové nanočástice * toxicita   chemie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• makrofágy účinky léků   imunologie   MeSH
• monocyty * účinky léků   imunologie   cytologie   MeSH
• nanočástice * toxicita   chemie   MeSH
• protein NLRP3 metabolismus   MeSH
• testy toxicity metody   MeSH
• titan * toxicita   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylmuramyl-alanyl-isoglutamin MeSH
• cytokiny MeSH
• inflamasomy MeSH
• interleukin-10 MeSH
• interleukin-1beta MeSH
• lipopolysacharidy MeSH
• NLRP3 protein, human MeSH Prohlížeč
• protein NLRP3 MeSH
• titan * MeSH
• titanium dioxide MeSH Prohlížeč