Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis.1

• Published in: The Journal of immunology (1950) 2012-06, Vol.189 (2), p.988-1001
• Main Authors: Berthier, Celine C, Bethunaickan, Ramalingam, Gonzalez-Rivera, Tania, Nair, Viji, Ramanujam, Meera, Zhang, Weijia, Bottinger, Erwin P., Segerer, Stephan, Lindenmeyer, Maja, Cohen, Clemens D., Davidson, Anne, Kretzler, Matthias
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1103031

Lupus nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these pre-clinical models. In this study we used an unbiased transcriptional network approach to define in molecular terms similarities and differences between three lupus models and human LN. Genome wide gene expression networks were generated using natural language processing and automated promoter analysis and compared across species via suboptimal graph matching. The three murine models and human LN share both common and unique features. The 20 commonly shared network nodes reflect the key pathologic processes of immune cell infiltration/activation, endothelial cell activation/injury and tissue remodeling/fibrosis, with macrophage/dendritic cell activation as a dominant cross-species shared transcriptional pathway. The unique nodes reflect differences in numbers and types of infiltrating cells and degree of remodeling between the three mouse strains. To define mononuclear phagocyte derived pathways in human LN, gene sets activated in isolated NZB/W renal mononuclear cells were compared with human LN kidney profiles. A tissue compartment specific macrophage activation pattern was seen, with NFκB1 and PPARγ as major regulatory nodes in the tubulointerstitial and glomerular networks respectively. Our study defines which pathologic processes in murine models of LN recapitulate the key transcriptional processes active in human LN and suggests that there are functional differences between mononuclear phagocytes infiltrating different renal microenvironments.