International Journal of Molecular Sciences Review Potential Synergistic Action of Bioactive Compounds from Plant Extracts against Skin Infecting Microorganisms Przemysław Sitarek 1,* , Anna Merecz-Sadowska 2 , Tomasz Kowalczyk 3 , Joanna Wieczfinska 4 , Radosław Zajdel 2 and Tomasz Sliwi´ ´nski 5 1 Department of Biology and Pharmaceutical Botany, Medical University of Lodz, 90-151 Lodz, Poland 2 Department of Economic Informatics, University of Lodz, 90-214 Lodz, Poland; [email protected] (A.M.-S.); [email protected] (R.Z.) 3 Department of Molecular Biotechnology and Genetics, University of Lodz, 90-237 Lodz, Poland; [email protected] 4 Department of Immunopathology, Medical University of Lodz, 90-752 Lodz, Poland; joanna.wieczfi[email protected] 5 Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland; [email protected] * Correspondence: [email protected] Received: 26 June 2020; Accepted: 16 July 2020; Published: 19 July 2020 Abstract: The skin is an important organ that acts as a physical barrier to the outer environment. It is rich in immune cells such as keratinocytes, Langerhans cells, mast cells, and T cells, which provide the first line of defense mechanisms against numerous pathogens by activating both the innate and adaptive response. Cutaneous immunological processes may be stimulated or suppressed by numerous plant extracts via their immunomodulatory properties. Several plants are rich in bioactive molecules; many of these exert antimicrobial, antiviral, and antifungal effects. The present study describes the impact of plant extracts on the modulation of skin immunity, and their antimicrobial effects against selected skin invaders. Plant products remain valuable counterparts to modern pharmaceuticals and may be used to alleviate numerous skin disorders, including infected wounds, herpes, and tineas. Keywords: plant extracts; immunological response; skin diseases; modulation of skin immunity; skin pathogens 1. Introduction Dermatological disorders are the fourth leading cause among nonfatal disability worldwide [1]. In family medicine, the prevalence of skin disease accounts for 12.4% of all disorders [2] and depends on sociodemographic circumstances [3]. Premature death associated with skin disorders is the 18th leading cause of health burden [4]. Bacteria, viruses, and fungi are common pathogens which affect skin. Fungal skin disease counts towards the top 10 most prevalent diseases globally, whereas bacterial (impetigo) and viral (molluscum contagiosum/warts) skin diseases are in the top fifteen [4]. The first line of defense is the epidermis, which acts as a physical barrier [5]. This is supported by the skin immune response, which reacts after wounding and infection [6]. The clinical manifestations and severity of skin infections varies according to disease. Medicinal plants have been used in traditional medicine for several thousand years in virtually all cultures. About 200 years ago, our pharmacopoeia was dominated by herbal medicines [7] and about Int. J. Mol. Sci. 2020, 21, 5105; doi:10.3390/ijms21145105 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 5105 2 of 25 25% of the natural compounds prescribed worldwide came from plants [8]. Historically, all medicinal preparations were derived from plants, whether as plant parts (leaf, rhizome, roots, stem, bark or fruits) or as crude extracts or mixtures. Plant extracts contain a number of bioactive compounds of different classes, including alkaloids, terpenoids, and polyphenols, possess numerous activities, such as antibacterial, antiviral, antifungal, antioxidant, anti-inflammatory, and anti-obesity [9–14], and have been used in various disorders, such as cardiovascular diseases, rheumatoid arthritis, osteoporosis, and skin diseases [15–19]. During the last few decades, the use of traditional medicine has expanded globally and has gained popularity as primary health care in developing countries, and in countries where conventional medicine is predominant [20]. Plant medicines also provide a rational means of treating many diseases that are incurable in other systems of medicine [21–24]. According to the World Health Organization (WHO), about 80% of the world’s population in developing countries depends essentially on plants for their primary healthcare and lack access to modern medicine. Additionally, of the 252 drugs considered as basic and essential by the WHO, 11% are exclusively of plant origin and a significant number are synthetic drugs obtained from natural precursors [25–27]. In dermatology, plants can have both beneficial and adverse effects on skin. The book “Botanical Dermatology” by Mitchell and Rook lists more than 10,000 species which cause irritative or allergic contact dermatitis [28]. Phytodermatitis is defined as inflammation of the skin caused by a plant. The clinical patterns may be allergic phytodermatitis, photophytodermatitis, irritant contact dermatitis, pharmacological injury, and mechanical injury [29,30]. The data supporting the use of phytotherapy are limited and therapies may not be regulated and standardized [31]. However, with the development of technology, it has become possible to determine the pharmacology and mechanisms of action of medical plants and they have already made fruitful contributions for modern medicine [20]. Moreover, about one-third of all traditional medicines are used to heal skin diseases, compared with just 1–3% of modern drugs [32–35]. A review of the literature published over the past five years indicates a number of plant extracts that demonstrate antibacterial, antifungal or antiviral activity against skin diseases. The aim of this study was to evaluate the role of plant extracts in the modulation of the cutaneous immunological response. It also examines their activity against selected skin pathogens, including bacteria, viruses, and fungi, with a focus on the molecular mechanisms of their action against skin invaders. 2. Immunological Response of the Skin The skin is the largest organ of the human body, and one which plays an important role in protecting the body from harmful exposure to external and internal environments. It is not only a physical barrier but also an immunological one. The cutaneous immune response involves keratinocytes and Langerhans cells (LCs) located in the outer layer, the epidermis, as well as mast cells residing in the dermis, and T cells in both layers [6]. They are responsible for innate and adaptive immunological reactions which promote cutaneous inflammation and memory response against antigens [36]. Innate immunity is a nonspecific rapid response, whose role is to activate phagocytes to neutralize microorganisms like bacteria, viruses, and fungi by phagocytosis [37]. In contrast, adaptive immunity is a long-lived process that requires interaction between T lymphocytes; these are subdivided into two groups, CD4 and CD8, depending on the presence of cell surface molecules and the cells presenting the antigens. This creates an immunological effector pathway specific for particular pathogens and initiation of the lymphocyte immunologic memory. These processes are crucial for maintaining immune homeostasis in the body and protect against harmful pathogens [38,39]. Keratinocytes, LCs, T lymphocytes, and mast cells express pathogen-recognition receptors (PRRs). Toll-like receptors (TLRs), members of that group, are involved in the host defense process against various pathogenic microorganisms. Thus far, thirteen TLRs have been identified in mammals. Each TLR detects different microbial components. TLR2/1 recognizes lipopeptides, TLRs 3/7/8/13 identify Int. J. Mol. Sci. 2020, 21, 5105 3 of 25 RNA, lipopolysaccharide (LPS) for TLR4, TLR5 recognize flagellin, TLR9 identify unmethylated CpG islands in DNA, profilin and Salmonella flagellin for TLR11, and profilin for TLR 12 [40,41]. Toll signaling pathways activate a wide range of genes via induction transcription factor NF-κB, AP-1, and interferon regulatory factors 3 and 7 (IRF3/7); these stimulate the expression of a variety of biologically active molecules. The most important secreted molecules are: tumor necrosis factor α (TNF); interleukins (IL) IL-1β, IL-6, IL-12 belonging to the cytokine family; IL-8, growth-regulated oncogene-α (GRO-α); monocyte chemoattractant protein (MCP) -1, -2, -3, -4; macrophage inflammatory protein-1 (MIP1) α/β; RANTES (regulated upon activation, normal T cell expressed and secreted) chemokine members; beta-defensins and cathelicidin antimicrobial agents; CD40, CD80 and CD86 co-stimulatory compounds; ICAM-1, which takes part in cell adhesion [42]. The adapter proteins include MyD88, Toll-interleukin 1 receptor domain-containing adapter protein (TIRAP), Toll-interleukin 1 receptor domain-containing adapter-inducing interferon-β (TRIF), and TRIF-related adapter molecule (TRAM). All TLRs, except TLR3, recruit MyD88. MyD88 initiates a downstream signaling cascade that results in the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP-1) and IRF3/7 and the expression of pro-inflammatory cytokines and antimicrobials. TIRAP and MyD88 are necessary for TLRs 2 and TLRs 4 initiation signaling of NFκB and mitogen-activated protein (MAP) kinases. TLR3 utilizes TRIF and especially stimulated IRF3/7, involved in the production of type I interferon (i.e., IFNα and IFNβ), which is important in the immune response against viruses.