Microarray Analyses Demonstrate the Involvement of Type I Interferons in Psoriasiform Pathology Development in D6-deficient Mice

• Published in: The Journal of biological chemistry 2013-12, Vol.288 (51), p.36473-36483
• Main Authors: Baldwin, Helen M., Pallas, Kenneth, King, Vicky, Jamieson, Thomas, McKimmie, Clive S., Nibbs, Robert J.B., Carballido, José M., Jaritz, Marcus, Rot, Antal, Graham, Gerard J.
• Format: Article
• Language: English
• Subjects: Animals; Chemokine Receptor D6; Chemokines; Cytokines/Interferon; Female; Immunology; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interferon Type I - genetics; Interferon Type I - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mouse; Oligonucleotide Array Sequence Analysis; Phorbol Esters - toxicity; Psoriasis; Psoriasis - chemically induced; Psoriasis - genetics; Psoriasis - immunology; Psoriasis - pathology; Receptors, CCR10 - genetics; Transcription, Genetic
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.491563

The inflammatory response is normally limited by mechanisms regulating its resolution. In the absence of resolution, inflammatory pathologies can emerge, resulting in substantial morbidity and mortality. We have been studying the D6 chemokine scavenging receptor, which played an indispensable role in the resolution phase of inflammatory responses and does so by facilitating removal of inflammatory CC chemokines. In D6-deficient mice, otherwise innocuous cutaneous inflammatory stimuli induce a grossly exaggerated inflammatory response that bears many similarities to human psoriasis. In the present study, we have used transcriptomic approaches to define the molecular make up of this response. The data presented highlight potential roles for a number of cytokines in initiating and maintaining the psoriasis-like pathology. Most compellingly, we provide data indicating a key role for the type I interferon pathway in the emergence of this pathology. Neutralizing antibodies to type I interferons are able to ameliorate the psoriasis-like pathology, confirming a role in its development. Comparison of transcriptional data generated from this mouse model with equivalent data obtained from human psoriasis further demonstrates the strong similarities between the experimental and clinical systems. As such, the transcriptional data obtained in this preclinical model provide insights into the cytokine network active in exaggerated inflammatory responses and offer an excellent tool to evaluate the efficacy of compounds designed to therapeutically interfere with inflammatory processes. Background: D6 regulates resolution of inflammatory responses. Its mode of action has not been molecularly defined. Results: Microarray analysis of inflamed D6-deficient mouse skin identifies dysregulated type I interferon responses as underpinning exaggerated inflammatory responses in D6-deficient mice. Conclusion: D6 is important for regulating type I interferon-based responses in inflammation. Significance: The study provides novel insights into roles for D6 in the resolution of inflammatory responses.