A novel mouse model expressing human forms for complement receptors CR1 and CR2
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RESEARCH ARTICLE
Open Access
A novel mouse model expressing human forms for complement receptors CR1 and CR2 Harriet M. Jackson1,2, Kate E. Foley1,3, Rita O’Rourke1, Timothy M. Stearns1, Dina Fathalla2, B. Paul Morgan2 and Gareth R. Howell1,3,4*
Abstract Background: The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer’s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known. Results: To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to here as CR1long and CR1short) can be replicated within this mouse model, along with a CR1 knockout allele (CR1KO). Transcriptional profiling of spleens and brains identified genes and pathways differentially expressed between mice homozygous for either CR1long, CR1short or CR1KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated by CR1long, but not CR1short or CR1KO. Conclusion: The B6.CR2CR1 mouse model provides a novel tool for determining the relationship between humanrelevant CR1 alleles and disease. Keywords: Complement cascade, Complement regulators, Immune cells, Alzheimer’s disease, Lupus, Hematopoietic cells, Immune cell infiltration
Background The complement cascade is an integral component of our innate immune response and a first line of defense against bacterial infections. Various components of the complement cascade are constantly surveying for invading pathogens or debris, and tagging them for destruction. This system is composed of a number of plasma * Correspondence: [email protected] 1 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, USA 3 Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA Full list of author information is available at the end of the article
and membrane bound proteins and is tightly regulated. Circulating complement components are produced in the liver but can also be produced by specific cells in tissues. In recent years, the recognized roles of the complement cascade have expanded. For example, the complement cascade is integral for the process of synapse pruning during development and disease [68, 70], for regulation of embryo survival [46, 84], and for tissue regeneration [19, 49, 66]. Many of these novel roles were
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