The Role of Skin and Orogenital Microbiota in Protective Immunity and Chronic Immune-Mediated Inflammatory Disease

Abstract

The skin and orogenital mucosae, which constitute complex protective barriers against infection and injuries, are not only the first to come into contact with pathogens but are also colonized by a set of microorganisms that are essential to maintain a healthy physiological environment. Using 16S ribosomal RNA metagenomic sequencing, scientists recognized that the microorganism colonization has greater diversity and variability than previously assumed. These microorganisms, such as commensal bacteria, affect the host's immune response against pathogens and modulate chronic inflammatory responses. Previously, a single pathogen was thought to cause a single disease, but current evidence suggests that dysbiosis of the tissue microbiota may underlie the disease status. Dysbiosis results in aberrant immune responses at the surface and furthermore, affects the systemic immune response. Hence, understanding the initial interaction between the barrier surface immune system and local microorganisms is important for understanding the overall systemic effects of the immune response. In this review, we describe current evidence for the basis of the interactions between pathogens, microbiota, and immune cells on surface barriers and offer explanations for how these interactions may lead to chronic inflammatory disorders.

Keywords: immune response; inflammation; microbiota; orogenital mucosa; skin mucosa.

Figure 1

Skin microbiota and immunity. (A) The microbiome is more diverse in healthy skin. Staphylococcus epidermidis, Acinetobacter spp., and Gram-positive anaerobe cocci (GPAC) exhibit protective features against atopic disease. Keratinocytes and sebocytes release antimicrobial peptides (AMPs), and associations with skin commensals, such as Propionibacterium spp., have been demonstrated. Pattern recognition receptors (PRRs), such as nucleotide-binding oligomerization domain containing 2, recognize bacterial peptidoglycans to increase AMP production. Skin commensals also control the expression of interleukin (IL)-1, and increased IL-1 production is followed by IL-17A and subsequent interferon-γ production by dermal T helper 17 and γδ T cells. Regulatory T (Treg) cells reside primarily around fair follicles and interact with commensals within a specific time window to achieve immune tolerance. In addition to classical Foxp3⁺ Treg cells, Foxp3⁻ Treg cells also interact with the bacterium Vitreoscilla filiformis to induce Foxp3⁻ Treg cell differentiation. (B) The dysbiosis induced by Leishmaniasis infection is not only transmissible but also exacerbates skin inflammation via neutrophil recruitment and production of IL-1β. (C) In atopic dermatitis, Staphylococcus aureus proliferates and microbial diversity decreases concomitantly. Additionally, along with epithelial barrier disruption, proinflammatory cytokines are produced. Activation of T cells to Th2 cells occur via two mechanisms: degranulation of mast cells from δ-toxin and downregulation of IP-10 and other Th1 cell-recruiting chemokines.

Figure 2

Oral microbiota and periodontal immunity. (A) The periodontium in healthy (left) and disease (right) states. When dysbiotic biofilm causes chronic inflammation of the gingiva, repeated swelling and inflammation results in deepening of the gingival sulcus, forming a subgingival periodontal pocket. The environment of the periodontal pocket intensifies the dysbiosis, and periodontal pathogens emerge. (B) A representative pathogen, Porphyromonas gingivalis, causes various immune responses that result in immune subversion and periodontitis. This organism inhibits secretion of IL-8 from gingival epithelial cells (GECs), interfering with the chemotaxis of neutrophils to the site of infection. Via the cysteine protease gingipain, P. gingivalis activates C5AR and toll-like receptor 2 (TLR2), triggering C5aR-TLR2 crosstalk. The crosstalk and cleavage of triggering receptor expressed on myeloid cells 1 (TREM-1) to soluble TREM-1 by gingipains result in simultaneous inhibition of phagocytosis and stimulation of inflammation. Gingipains also increase IL-33 production from GECs, downregulating antimicrobial peptides (AMPs) and increasing osteoclastogenecity. In macrophages, the C5aR-TLR2 crosstalk works to inhibit P. gingivalis degradation by suppressing production of nitric oxide and IL-12 without disruption of proinflammatory properties. The downregulation of IL-12 is also potentiated by binding of P. gingivalis to complement receptor 3.

Figure 3

Vaginal microbiota and immunity. (A) The vaginal microbiota in a healthy individual is dominated by Lactobacillus spp. The Lactobacillus spp. produce lactic acid as well as antimicrobial compounds to control the growth of microbes. Other soluble factors, such as antimicrobial peptides (AMPs), mannose-binding lectins (MBLs), and immunoglobulins (Igs), contribute to the homeostatic immunity of the vaginal surface. In addition, the surveillance of commensals and pathogenic microbes is achieved by pattern recognition receptors (PRRs). (B) In cases of disrupted vaginal microbiota, such as bacterial vaginosis, community state type IV type microorganisms dominate to initiate an inflammatory response. Short-chain fatty acids produced by these microorganisms are likely to induce the production of proinflammatory cytokines. IL-33 has recently been identified as the key cytokine in association with antiviral immunity modulation by the vaginal microbiome. IL-33 is also responsible for the Th2-type immune response elicited by proteases that are secreted by pathogenic microbes.