Differential Effects of Peptidoglycan Recognition Proteins on Experimental Atopic and Contact Dermatitis Mediated by Treg and Th17 Cells Shin Yong Park1, Dipika Gupta1*, Chang H. Kim2, Roman Dziarski1* 1 Indiana University School of Medicine–Northwest, Gary, Indiana, United States of America, 2 School of Veterinary Medicine, Purdue University, West Lafayette, Indiana, United States of America 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. Pglyrp32/2 and Pglyrp42/2 mice (but not Pglyrp22/2 mice) develop more severe oxazolone-induced atopic dermatitis than wild type (WT) mice. The common mechanism underlying this increased sensitivity of Pglyrp32/2 and Pglyrp42/2 mice to atopic dermatitis is reduced recruitment of Treg cells to the skin and enhanced production and activation Th17 cells in Pglyrp32/2 and Pglyrp42/2 mice, which results in more severe inflammation and keratinocyte proliferation. This mechanism is supported by decreased inflammation in Pglyrp32/2 mice following in vivo induction of Treg cells by vitamin D or after neutralization of IL-17. By contrast, Pglyrp12/2 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. Citation: Park SY, Gupta D, Kim CH, Dziarski R (2011) Differential Effects of Peptidoglycan Recognition Proteins on Experimental Atopic and Contact Dermatitis Mediated by Treg and Th17 Cells. PLoS ONE 6(9): e24961. doi:10.1371/journal.pone.0024961 Editor: Samithamby Jeyaseelan, Louisiana State University, United States of America Received April 19, 2011; Accepted August 24, 2011; Published September 16, 2011 Copyright: 2011 Park et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by United States Public Health Services Grants AI028797 and AI073290 from the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: dgupta@iun.edu (DG); rdziar@iun.edu (RD) Introduction 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 and contact dermatitis are among the most frequent inflammatory skin diseases, both determined by multigenic predisposition, environ- mental factors, and aberrant immune response. 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 hyper- sensitivity to environmental allergens, and is manifested by pruritic erythematosus skin eruptions and increased IgE response, often with aggravating bacterial infections [1–3]. Allergic contact dermatitis (contact hypersensitivity) has a prevalence of 2–20% and involves type IV (delayed-type) hypersensitivity to environ- mental allergens, manifested by erythematosus skin infiltrations with inflammatory cells [2,4,5]. 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. Mammals have four PGRPs, Pglyrp1, Pglyrp2, Pglyrp3, and Pglyrp4, which were initially named PGRP-S, PGRP-L, PGRP-Ia, and PGRP-Ib, respectively [6,7]. Three PGRPs, Pglyrp1, Pglyrp3, and Pglyrp4 are directly bactericidal [8–11], whereas Pglyrp2 is an N- acetylmuramoyl-L-alanine amidase that hydrolyzes peptidoglycan [12,13]. Pglyrp1 is highly expressed in PMN’s granules and to a much lower extent in other cells [7,14,15]. Pglyrp2 is constitutively expressed in the liver and secreted into blood, and its expression is induced in keratinocytes and other epithelial cells [12,13,16–20]. Pglyrp3 and Pglyrp4 have the highest expression in the skin and are also expressed in the salivary glands, throat, tongue, esophagus, stomach, intestine, and eyes [8,21,22]. Similar to Pglyrp1 and Pglyrp2, Pglyrp3 and Pglyrp4 are secreted and their expression in these tissues is both constitutive and inducible. We hypothesized that PGRPs play a role in the development atopic dermatitis and contact dermatitis because of (a) the prominent expression of PGRPs in the skin, (b) the location of Pglyrp3 and Pglyrp4 genes in the epidermal differentiation gene cluster in the psoriasis sensitivity psors4 locus, (c) coordinated expression of Pglyrp3 and Pglyrp4 with other genes in the psors4 locus, (d) previous evidence of genetic association of Pglyrp3 and Pglyrp4 variants with psoriasis, which is another genetically- and environmentally-determined skin disease [23,24], and (e) the ability of mammalian PGRPs to protect mice against experimental PLoS ONE | www.plosone.org 1 September 2011 | Volume 6 | Issue 9 | e24961