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

TY - JOUR

T1 - Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis

AU - Berthier, Celine C

AU - Bethunaickan, Ramalingam

AU - Gonzalez-Rivera, Tania

AU - Nair, Viji

AU - Ramanujam, Meera

AU - Zhang, Weijia

AU - Bottinger, Erwin P

AU - Segerer, Stephan

AU - Lindenmeyer, Maja

AU - Cohen, Clemens D

AU - Davidson, Anne

AU - Kretzler, Matthias

PY - 2012/7/15

Y1 - 2012/7/15

N2 - Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these preclinical models. In this study, we used an unbiased transcriptional network approach to define, in molecular terms, similarities and differences among 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 among 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 NF-κB1 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.

AB - Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these preclinical models. In this study, we used an unbiased transcriptional network approach to define, in molecular terms, similarities and differences among 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 among 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 NF-κB1 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.

KW - Animals

KW - Crosses, Genetic

KW - Disease Models, Animal

KW - Gene Expression Profiling

KW - Gene Regulatory Networks

KW - Glomerulonephritis, IGA

KW - Humans

KW - Inflammation

KW - Lupus Nephritis

KW - Male

KW - Mice

KW - Mice, Inbred NZB

KW - Nephritis, Interstitial

KW - Proteinuria

KW - Transcription, Genetic

KW - Comparative Study

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.4049/jimmunol.1103031

DO - 10.4049/jimmunol.1103031

M3 - SCORING: Journal article

C2 - 22723521

VL - 189

SP - 988

EP - 1001

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 2

ER -