Toll-like receptors (TLR) are mammalian homologues of Toll receptors, which were first defined in Drosophila. According to Kim et al,1 TLR are one example of pattern recognition receptors of the innate immune system. TLR are involved in host defenses against bacteria, fungi, and parasites.1 These receptors are expressed on skin and airway epithelium in addition to immune cells, including monocytes, macrophages, dendritic cells, and granulocytes. There are at least 10 TLR in humans.

According to McInturff et al,2 are “transmembrane proteins with the extracellular portion composed of leucine-rich repeats, whereas the intracellular portion shares homology with the cytoplasmic domain of the IL-1 receptor.” The activation of TLR by ligand exposure leads to the nuclear translocation of the transcription factor NFκB, which, in turn, modulates the expression of many immune response genes. This results in the formation of a multitude of cytokines and chemokines. Other effects of TLR activation include the release of antimicrobial peptides and the facilitation of adaptive immunity.2 This commentary will focus on the role of TLR in the pathogenesis of acne vulgaris.
Harper and Thiboutot3 state that the etiologic factors of acne are mutifactorial, including ductal epidermal hyperproliferation, excess sebum, inflammation, and the presence of Proprionobacterium acnes.

Knor4 states that “increased sebum production and follicular hyperkeratosis result in the development of microcomedones, and changes in follicular milieu in intensive growth of P acnes. P acnes secretes several proinflammatory products, which play an important role in the development of inflammation. These include lipases, proteases, hyaluronidases, and chemotactic factors. Immune responses to P acnes include humoral and cell-mediated immunity as well as complement activation.” Keratinocytes and sebocytes, as major components of the pilosebaceous unit, may act as immune cells and may be activated by P acnes via TLR and its coreceptor CD14.4
Kim et al1 inquired as to whether TLR2 mediates P acnes–induced cytokine production in acne. They determined that transfection of TLR2 into a nonresponsive cell line was sufficient for NFκB activation in response to P acnes.

Other results in their study that implicate the involvement of TLR2 in acne include: (1) P acnes–induced activation of interleukin (IL)-12 p40 promoter activity via TLR2; (2) P acnes–induced IL-12 and IL-8 protein production by primary human monocytes which is inhibited by anti-TLR2 blocking antibody; and (3) the demonstration of TLR2 expression on the cell surface of macrophages surrounding pilosebaceous follicles taken from acne lesions. This data suggests that P acnes triggers inflammatory cytokine responses in acne by activation of TLR2.1

Jugeau et al5 studied the effect of P acnes upon TLR activation in keratinocytes. They found that in vivo, TLR2 and TLR4 expression is increased in the epidermis of acne lesions. In vitro, an increase in both TLR2 and TLR4 expression by human keratinocytes occurred in the first hours of incubation with bacterial fractions, as well as an increase in the expression and secretion by the keratinocytes of matrix metalloproteinase-9, which has a role in the inflammatory process. The authors concluded that the P acnes induction of TLR expression may be vital in the inflammation observed in acne.5
Nagy et al6 investigated the capability of four different strains of P acnes to activate the innate immune response and the growth of keratinocytes. They found that two of four clinical isolates of P acnes significantly induced human beta-defensin-2 mRNA expression and that all four strains significantly induced IL-8 expression; all of these effects could be inhibited by anti-TLR2 and anti-TLR4 neutralizing antibodies. Additionally, one isolate of P acnes was capable of inducing keratinocyte growth in vitro. Presumptively, these findings may be relevant to the ductal hypercornification and inflammatory processes involved in the pathogenesis of acne vulgaris.6

Acne therapy may have its effect via TLR. Liu et al7 demonstrated that the treatment of primary human monocytes with all-trans retinoic acid led to the down-regulation of TLR2 and its coreceptor CD14, but not TLR1 or TLR4. Not only may current acne treatments at least partially have their therapeutic effect via TLR, but novel therapies may be developed to take advantage of the inflammatory events modulated by TLR. The authors note that “already, certain lipid A analogues have been reported to antagonize TLR2 and TLR4 activation through interaction with shared receptor components, resulting in the loss of tumor necrosis factor-α secretion but not nitric oxide production in both transfected cell lines as well as primary human alveolar macrophages.”7

Much remains to be learned about the pathogenesis of acne regarding the role of P acnes and TLR. The burgeoning knowledge of TLR and its effect on innate immunity are modifying our concepts regarding comedogenesis and inflammation that results in clinical acne lesions. These discoveries may enable the development of innovative medications for acne vulgaris, ranging from mild comedonal to severe, cystic, scarring disease.

Autor: Heymann WR

Fonte: J Am Acad Dermatol; 55(4): 691-2, 2006 Oct.

Publicado por Dr. Emmanuel França