Date Published: March 4, 2019
Publisher: Public Library of Science
Author(s): Federica De Santis, Noemi Poerio, Angelo Gismondi, Valentina Nanni, Gabriele Di Marco, Roberto Nisini, Maria Cristina Thaller, Antonella Canini, Maurizio Fraziano, Olivier Neyrolles.
In nature, many plants or their extracted compounds have been found to possess anti-inflammatory features and therapeutic properties against infectious as well as non-infectious diseases, including cancer. In this study, we analysed the immunomodulatory effects on innate immune cells of hydroalcoholic extract from Origanum vulgare L. ssp. hirtum (HyE-Ov), a plant traditionally known for its anti-oxidative properties. The effects of HyE-Ov were tested on human monocyte derived dendritic cells (DC), type-1 (M1) and type-2 macrophages (M2) infected with M. bovis Bacille Calmette-Guérin (BCG), used as a model of persistent intracellular bacterium. DC, M1 and M2 treated with HyE-Ov significantly enhanced their mycobactericidal activity, which was associated with phagosomal acidification in M1 and M2 and increase of phagosomal, but not mitochondrial ROS production in M1, M2, and DC. Treatment of BCG-infected DC with HyE-Ov significantly reduced TNF-α and IL-12 production and increased TGF-β synthesis. Finally, experiments were repeated using eight different HPLC fractions of HyE-Ov. Results showed that the capability to activate anti-microbial and anti-inflammatory response is shared by different fractions, suggesting that diverse bioactive molecules are present within the hydroalcoholic extract. Altogether, these results show that HyE-Ov promotes anti-mycobacterial innate immunity and limits inflammatory response in vitro and suggest that this plant extract may be exploitable as phytocomplex or nutraceutical for novel host-directed therapeutic approaches.
Since ancient times, man has used plants to obtain therapeutic benefits and there is now an increasing scientific interest for their biological properties as they can provide a plethora of novel molecules of pharmacological interest . An assessment of all Food and Drug Administration (FDA)- and European Medicine Agency (EMA)-approved molecules reveals that natural products and their derivatives represent over one-third of all new molecules, with one quarter of them derived from plants  as they may contain a variety of biologically active secondary metabolites with possible therapeutic value against infectious as well as non-infectious diseases and cancer [1, 3–5]. Among plants of potential medical interest, O. vulgare L. is known for its properties as expectorant, antimicrobial and carminative . Origanum genus belongs to the Lamiaceae family and most of its species are distributed around the Mediterranean area, Eurasia and the North of Africa, where it is used in traditional medicine for the treatment of cold, cough, digestive and respiratory disorders [6, 7].
All biomolecules, either of natural or of synthetic origin, able to suppress or stimulate the immune system, are known as immunomodulators and the interest for their identification among plants is increased during the last years . In fact, plants or their extracts may represent a source of products with immunomodulatory activity and, as such, can be used as nutraceuticals, substances that have a beneficial effect on health, or in phytotherapy, an ancient practice consisting of use of plants for the prevention or treatment of diseases. A number of studies have described significant anti-inflammatory activity and direct bactericidal properties of O. vulgare derived essential oils , but issues concerning tolerability and toxicities limited its uses in human subjects . Water soluble, hydroalcoholic and methanolic extracts of the plant, which are normally characterized by good tolerability, have also been reported to show anti-inflammatory, anti-oxidant and direct bactericidal features [16, 17]. However, studies on the identification of plant extracts capable to promote antimicrobial activity in innate immune cells by simultaneously limiting potentially tissue-damaging inflammatory response are still lacking. In the present study, we showed the capability of HyE-Ov to enhance anti-microbial response of innate immune cells, such as dendritic cells, type-1 and type-2 macrophages in a model of in vitro BCG infection. These cell types have been used as they are the preferential targets of Mycobacterium tuberculosis  and a correct balance in the response of these different cell types in the granuloma is necessary both to control the infection and to limit the tissue damage . Despite of differences in intracellular mycobacterial replication among the different cell types [38, 39], HyE-Ov stimulation leads to a significant reduction of intracellular mycobacterial growth in all cell types, independently by the MOI used and by the basal anti-mycobacterial response.