Abstract
The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
Platelet Recruitment in Glomerulonephritis
Leukocyte recruitment to the glomerulus contributes to the pathogenesis of glomerulonephritis. Platelets also accumulate in the capillaries of the glomerulus during disease development, where they enhance leukocyte recruitment. To elucidate the mechanisms governing platelet recruitment as well as their contribution to leukocyte recruitment in glomerulonephritis, Devi et al (Am J Pathol 2010, 177:1131–1142) used intravital microscopy to follow disease progression. Platelets were recruited within 5 minutes of disease initiation, and recruitment was dependent on both the collagen receptor GPVI and αIIbβ3 integrin, which interacts with the extracellular matrix component fibrinogen. In addition, platelet but not endothelial expression of P-selectin was responsible for leukocyte recruitment to the glomerulus. Therefore, platelets have a central role in leukocyte recruitment in glomerulonephritis.
Integrin-7α Functions as a Tumor Suppressor in Prostate Cancer
Integrin-7α, an adhesion molecule that interacts with the extracellular matrix, is commonly mutated in prostate cancer. Zhu et al (Am J Pathol 2010, 177:1176–1186) report that integrin-7α expression induces cell death in prostate cancer cell lines through its interaction with high temperature requirement A2 (HtrA2). HtrA2 is a serine protease that plays a role in apoptosis, and interaction with integrin-7α increases its protease activity. Indeed, disrupting the interaction between integrin-7α and HtrA2, either by deleting the interaction domain or decreasing levels of HtrA2, inhibits apoptosis in these cells. In contrast, interaction of integrin-7α with its ligand, laminin 2, prevents this apoptotic function. Thus, unbound integrin-7α may act as a tumor suppressor in prostate cancer.
Osteopontin Affects Bacterial Attachment in Intestinal Disease
The cytokine osteopontin is highly expressed in autoimmune and inflammatory diseases, including inflammatory bowel disease; however, the role of osteopontin in disease pathogenesis remains controversial. Wine et al (Am J Pathol 2010, 177:1320–1332) used an infectious animal model of colitis, Citrobacter rodentium infection, to study the effects of ostepontin expression on host responses to a bacterial pathogen. They found that C. rodentium infection increased osteopontin expression and that osteopontin deficiency reduced levels of colonic epithelial cell hyperplasia and inhibited spleen enlargement, both hallmarks of infection. Bacterial adhesion and colonization were also decreased in a manner dependent on osteopontin. These data suggest that osteopontin may influence disease pathogenesis by altering bacterial adhesion and host response, which may form the basis for altered bacteria-gut interactions in inflammatory bowel disease.
Synchronized Model of Chronic Rheumatoid Arthritis
Rheumatoid arthritis, characterized by chronic inflammation of the distal joints, is mediated in part by emigration and activation of macrophages and monocytes. The restrictions of present models, which either mimic chronic disease or allow a synchronized initiation of disease but not both, have limited study of the roles of inflammatory cells and their mediators in disease initiation and maintenance. Therefore, LaBranche et al (Am J Pathol 2010, 177:1388–1396) have developed a chronic, synchronized model of rheumatoid arthritis. Disease in these animals developed with a uniform onset of 7 days post-initiation and was maintained chronically. These mice revealed a time course of rheumatoid arthritis characteristics, including edema, immune cell infiltration, and cartilage destruction. This model therefore provides a novel and easily manipulated means to elucidate further the roles of inflammatory cells in rheumatoid arthritis as well as to validate therapeutic targets.
Mitochondrial Dysfunction Correlates with Synaptic Loss in Prion Disease
Prions are pathogenic misfolded proteins that cause severe neurological diseases such as bovine spongiform encephalopathy (mad cow disease) and Creutzfeldt-Jakob disease. To explore the mechanisms by which prions result in synaptic loss, Sisková et al (Am J Pathol 2010, 177:1411–1421) examined the morphology and function of mitochondria within affected neurons. Although similar numbers of mitochondria were present in affected and unaffected neurons, mitochondrial function was impaired in prion-infected animals when compared with uninfected controls. Moreover, there were structural changes in the mitochondrial inner membrane morphology as well as altered levels of proteins in the respiratory chain complex. As these changes were evident early in disease progress, mitochondrial dysfunction may contribute to pathogenesis in prion-related neuropathy.