Abstract
Skin protects the body from the environment and is an important component of the innate and adaptive immune systems. Atopic dermatitis and contact dermatitis are among the most frequent inflammatory skin diseases and are both determined by multigenic predisposition, environmental factors, and aberrant immune response. Peptidoglycan Recognition Proteins (Pglyrps) are expressed in the skin and we report here that they modulate sensitivity to experimentally-induced atopic dermatitis and contact dermatitis. Pglyrp3 −/− and Pglyrp4 −/− mice (but not Pglyrp2 −/− mice) develop more severe oxazolone-induced atopic dermatitis than wild type (WT) mice. The common mechanism underlying this increased sensitivity of Pglyrp3 −/− and Pglyrp4 −/− mice to atopic dermatitis is reduced recruitment of Treg cells to the skin and enhanced production and activation Th17 cells in Pglyrp3 −/− and Pglyrp4 −/− mice, which results in more severe inflammation and keratinocyte proliferation. This mechanism is supported by decreased inflammation in Pglyrp3 −/− mice following in vivo induction of Treg cells by vitamin D or after neutralization of IL-17. By contrast, Pglyrp1 −/− mice develop less severe oxazolone-induced atopic dermatitis and also oxazolone-induced contact dermatitis than WT mice. Thus, Pglyrp3 and Pglyrp4 limit over-activation of Th17 cells by promoting accumulation of Treg cells at the site of chronic inflammation, which protects the skin from exaggerated inflammatory response to cell activators and allergens, whereas Pglyrp1 has an opposite pro-inflammatory effect in the skin.
Highlights
Skin protects the body from the environment and is the largest organ in mammals
These results indicate that in wild type (WT) mice both Pglyrp3 and Pglyrp4 have a protective effect against severe atopic dermatitis-like inflammation, whereas Pglyrp1 has an enhancing proinflammatory effect and Pglyrp2 has little effect on the response to oxazolone
Pglyrp2 played a minor role, because Pglyrp22/2Pglyrp32/2 double-knockout mice and Pglyrp12/2Pglyrp22/2Pglyrp32/2 and Pglyrp12/2Pglyrp22/2 Pglyrp42/2 triple-knockout mice had higher serum IgE levels than Pglyrp32/2 and Pglyrp42/2 single-knockout mice. These results demonstrate that deletion of Pglyrp3 or Pglyrp4 highly predisposes mice to atopic dermatitis-like lesions in response to oxazolone, and in WT mice Pglyrp3 or Pglyrp4 protect the skin from excessive inflammation in the oxazolone model of atopic dermatitis
Summary
Skin protects the body from the environment and is the largest organ in mammals. Besides forming a mechanical barrier, skin is an important component of the innate and adaptive immune systems rich in anti-microbial peptides and antigen-sensing cells, and it maintains the proper homeostatic balance between pro- and anti-inflammatory responses. Atopic dermatitis has a prevalence of 15–30% in children and 2–10% in adults, involves loss of barrier function of the skin and type I hypersensitivity to environmental allergens, and is manifested by pruritic erythematosus skin eruptions and increased IgE response, often with aggravating bacterial infections [1,2,3]. Peptidoglycan Recognition Proteins (PGRPs or Pglyrps) are a family of innate immunity proteins expressed in the skin. PGRPs are conserved from insects to mammals, recognize bacterial peptidoglycan, and function in antibacterial immunity. Pglyrp is constitutively expressed in the liver and secreted into blood, and its expression is induced in keratinocytes and other epithelial cells [12,13,16,17,18,19,20]. Similar to Pglyrp and Pglyrp, Pglyrp and Pglyrp are secreted and their expression in these tissues is both constitutive and inducible
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