Lymphocytes are important in early atherosclerosis

Abstract

Lymphocytes represent a potentially important proinflammatory cell that localizes to atherosclerotic lesions. To determine whether they contribute to lesion development, atherosclerosis-prone (LDLR -/-) mice were crossed with lymphocyte-deficient (RAG1 -/-) mice to generate double knockout progeny. After 8 weeks on a Western-type diet (WTD), lesion development was reduced by 54% in double knockout mice, as compared with matched LDLR -/-controls. However, these significant differences in lesion area gradually subsided as the WTD was continued for 12 and 16 weeks. Consistent with this observation, histological studies determined that lesion initiation and early progression were delayed in RAG1/LDL-R double knockout mice. Differences in lesion area did not correlate with any significant alterations in plasma lipid levels. These studies suggest that lymphocytes play an important role early in atherogenesis. mice were crossed with the RAG1-null mice, and atherogenesis was evaluated. Although atherosclerotic lesions were small after 4 weeks on a Western type diet (WTD), they had grown significantly by 8 weeks. Moreover, they were 54% smaller in the RAG1/LDL-R double knockout mice, suggesting lymphocyte function is important at this point in time. Lesions continued to grow with time, but the relative difference in lesion area between LDL-R-null and RAG1/LDL-R double knockout mice became less significant. These results indicate that lymphocytes play a more important role early in the pathogenesis of atherosclerotic lesions. MethodsMice. The LDL-R-null mice (in a C57BL/6 background) and RAG1-null mice (in a C57BL/6 background) were obtained from The Jackson Laboratory (Bar Harbor, Maine, USA). Mice, maintained in a specific pathogen-free facility, were interbred and genotyped by PCR as described previously (32-34). Once sufficient numbers of single-and double knockout mice were available (i.e., about ten age-and sex-matched mice for each group), they were placed on a WTD (21% fat, 0.15% cholesterol for 4-16 weeks; Harlan Teklad Laboratory, Winfield, Iowa, USA). Hearts and fasted plasma samples were collected from sacrificed mice.Histochemistry. Hearts were perfused with PBS, embedded in OCT, and snap-frozen. Then 10-µm-thick transverse sections covering 350-400 µm of the proximal aorta were collected. For atherosclerosis quantitation, every sixth section (for a total of six sections) was stained with Oil red O after fixation in 4% paraformaldehyde. Lesion area was then determined by measuring accumulated intimal lipid by video microscopy, as described previously (35-37). To evaluate lesion cellularity, nuclei were counted in serial sections that had been stained with Oil red O. Alternating sections were stained with either hematoxylin and eosin (H&E) or Trichrome after the fixation in 4% formaldehyde (22). Collagen content was determined by measuring the accumulated collagen in serial Trichrome-stained sections, as described above.Immunohistochemistry. Cold acetone fixed frozen sections were stained with an MHC-II-specif...

IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

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Using Mice to Dissect Genetic Factors in Atherosclerosis

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Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction

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