The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis

Figure 2

Proposed model for the role of TLR-mediated innate immune events in regulating the Th1/Th17 and Th2 immune balance. The development of Th1/Th17 T cells can be initiated upon innate immune activation of several TLRs, including TLR3 and MAVS (mitochondrial antiviral signaling protein) in keratinocytes (KCs), TLR7 and TLR9 in pDCs, TLR8 in cDCs, TLR2 in KCs and monocytes (Mon), and TLR4 in monocytes. Activation of these TLR-mediated signaling events leads to elevated expression of proinflammatory cytokines, type 1 interferons (including IFNβ from KCs and IFNα from pDCs), antimicrobial peptides (AMP), and costimulatory molecules (on cDCs and pDCs), which ultimately promote the differentiation of T cells from the Th0 to Th1/Th17 phenotype. In contrast, impaired TLR2 may play a role in the development of Th2 immune response. Genetic factors (such as TLR2 polymorphisms) or lack of early childhood exposure to microbes impairs TLR2 expression, and the resultant defective TLR2 signaling leads to decreased expression of antimicrobial peptides (AMPs), compromised epithelial barrier integrity, and decreased expression of Th1/Th17 cytokines. Impaired barrier integrity plays a central role in driving the allergic Th2 immune response by allowing allergens to penetrate through the skin surface. In addition, lack of AMP expression in the skin epidermis promotes dysbiosis of the skin microbiome and overgrowth of S. aureus, which releases several virulent toxins that exacerbate the disruption of barrier integrity and the expression of inflammatory Th2 cytokines. Activation of the Th1/Th17 immune system is necessary to promote autoimmunity and host defense against pathogens and cancer cells, but overstimulation of the Th1/Th17 pathway drives the development of several autoimmune diseases, including psoriasis, systemic lupus erythematosus (SLE), and fibrotic skin diseases (e.g., hypertrophic scarring and systemic sclerosis (SSc)). On the other hand, activation of the Th2 immune system is necessary to elicit normal allergic immune responses to allergens or pathogens, but overstimulation of Th2 immune response early in life initiates the progression of allergic diseases including atopic dermatitis, asthma, and allergic rhinitis, a pathological process known as “atopic march.”