Macrophage inflammatory protein 3α deficiency in atopic dermatitis skin and role in innate immune response to vaccinia virus

Background: Patients with atopic dermatitis (AD) are prone to disseminated viral skin infections and therefore are not vaccinated against smallpox because of potential complications. Macrophage inflammatory protein 3 alpha (MIP-3 alpha) is a C-C chemokine expressed by keratinocytes that exhibits antimicrobial activity against bacteria and fungi; however, its role in antiviral innate immunity is unknown. Objective: Evaluate the level of MIP-3a in AD skin and its role in the innate immune response to vaccinia virus (VV). Methods: Macrophage inflammatory protein 3a levels were evaluated using real-time RT-PCR, immunodot-blot, and immunohistochemistry. The antiviral activity of MIP-3a was determined using a standard viral plaque assay. Results: Macrophage inflammatory protein 3a gene expression was significantly (P < .01) decreased in AD skin (< .21 +/- 0.05 ng MIP-3 alpha/ng glyceraidehyde-3-phosphate dehydrogenase) compared with psoriasis skin (0.67 +/- 0.13). This was confirmed at the protein level using immunohistochemistry. We further demonstrate that T(H)2 cytokines downregulate MIP-3a expression. The importance of MIP-3 alpha in the innate immune response against VV was established by first demonstrating that MIP-3a exhibits activity against VV. Second, VV replication was significantly increased (P < .01) in keratinocytes treated with an antibody to neutralize MIP-3 alpha. Conclusion: The current study demonstrates that MIP-3 alpha exhibits antiviral activity against VV and demonstrates the importance of MIP-3 alpha in the innate immune response against VV. In addition, AD skin is deficient in MIP-3 alpha, in part because of the overexpression of T(H)2 cytokines in AD skin. Clinical implications: MIP-3 alpha deficiency in AD skin contributes to patients' increased propensity toward eczema vaccinatum. Increasing MIP-3 alpha or neutralizing T(H)2 cytokines could prevent adverse reactions in patients with AD after smallpox vaccination.