Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Transcriptional Inflammatory Mechanism in Murine Lupus Nephritis: An Insight into Human Disease.
Rivera3, Tania C. Gonzalez, Berthier3, Celine C., Nair3, Viji, Bethunaickan1, Ramalingam, Kretzler3, Matthias, Davidson2, Anne, ERCB Consortium,
Despite advances in immunosuppressive regimens, lupus nephritis (LN) remains a significant cause of morbidity and mortality in lupus patients. Murine LN models have been used to study this heterogeneous disease but the failure of human trials to reproduce the results seen in mice has raised concerns whether these models truly reflect human disease. Using a transcriptional network comparison we aim to define similarities and differences between three LN murine models and human LN.
Affymetrix based expression profiles from prenephritic vs. nephritic kidneys from 3 LN mouse models (NZB/W, NZM2410, and NZW/BXSB, total n=40) and human renal biopsies from 15 living donors (LD) vs. 32 LN patients underwent disease model specific transcriptional network analysis (Bibliosphere).
Transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE) to define cross-species conserved functional interactions. The NZM2410 model shared the highest number of nodes with human LN, followed by the NZB/W and the NZW/BXSB models (70, 46 and 37 major transcriptional network nodes, respectively). Pathway analysis of the 17 nodes shared by the human and murine models highlighted macrophage activation pathways (p<0.001).
To distinguish the components of the macrophage-specific signature that were due to an alteration in cell phenotype rather than to infiltration with increased numbers of cells per se, gene expression profiles of macrophages isolated from prenephritic and nephritic NZB/W kidneys were generated and compared with corresponding murine and human LN kidney profiles. A total of 406 transcripts were concordantly regulated between NZB/W kidney isolated macrophages and whole kidneys. Of those, 132 transcripts were regulated in the tubulointerstitium of human LN kidneys, consistent with macrophage-derived expression. This signature was used to define the transcriptional state of kidney resident macrophages in murine and human LN. Network analysis defined Stat3, Anxa2 and TIMP1 as major hubs in the network. Application of the MESH filter "macrophage activation" on the network highlighted Lyn, Spp1 and CD44.
The response of tissue resident macrophages to treatment was assessed in NZB/W mice treated with cyclophosphamide/CTLA4Ig/anti-CD154. From the defined renal macrophage signature, Lyn, Anxa2, and CD44 were major hubs of repressed genes in isolated kidney resident macrophages with induction of remission (histologic remission and absence of proteinuria) with triple therapy.
We were able to define key regulators of inflammation shared between human and murine LN using an integrative transcriptional network analysis approach. Given the similarities between mice and humans highlighted by our studies, therapeutic agents that target macrophage activation should represent a focus in the development of therapies for human LN.
To cite this abstract, please use the following information:
Rivera, Tania C. Gonzalez, Berthier, Celine C., Nair, Viji, Bethunaickan, Ramalingam, Kretzler, Matthias, Davidson, Anne, et al; Transcriptional Inflammatory Mechanism in Murine Lupus Nephritis: An Insight into Human Disease. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2276