NOD2 deficiency exacerbates imiquimodinduced, psoriasis-like dermatitis

Abstract Nucleotide-binding oligomerization domain containing protein 2 (NOD2) is a CARD domain-containing pattern recognition protein in which inactivating mutations can cause Crohn’s disease. Mechanisms that have been suggested to explain the inflammation in Crohn’s disease associated with loss of NOD2 function include inadequate intestinal antibacterial defense or, on the other hand, diminished inhibition of toll-like receptor (TLR) signaling. Psoriasis is a common autoimmune skin disease for which recent data show significant up-regulation of NOD2 in keratinocytes of the lesional skin. We investigated a role for NOD2 in a TLR-driven mouse model of psoriasis-like dermatitis in which IL-17A and IL-22 are critical contributors. Following topical application of the TLR7/8 agonist, imiquimod, as compared with wild-type controls, Nod2−/− mice showed increases in epidermal thickness, epidermal neutrophils, and numbers of α/β and γ/δ T cells capable of producing IL-17A and IL-22 as well as expression of mRNAs for IL-17 and IL-22 in the treated skin. In addition, we found increased levels of mRNAs for IL-1β, and for several IL-1-inducible proteins, including COX2 and the neutrophil chemoattractants CCL3, CXCL2, and CXCL3, and decreased levels of mRNA for IL-1RA in the imiquimod-treated skin of the Nod2−/− mice. Taken together, these data suggest that NOD2 may be limiting skin inflammation in psoriasis by regulating IL-1/TLR signaling, supporting an important immunomodulatory role for NOD2 in inflammatory disease.