Relationship between CCL22 Expression by Vascular Smooth Muscle Cells and Macrophage Histamine Receptors in Atherosclerosis

Abstract

Aim: CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines and is involved in monocyte migration and recruitment. We have previously investigated CCL22 and histamine in atherosclerosis. Here, we investigated the hypothesis that CCL22 is involved in atherosclerosis, which is influenced by the differentiation of macrophage phenotypes via histamine.Methods: CCL22 expression was investigated in human carotid arteries and coronary arteries with bare metal stents. Ligated carotid arteries of wild-type (C57BL/6J) and apolipoprotein E-deficient mice were also used as atherosclerotic models. The localization and expression of CCL22 and classical (M1)-like and M2-like macrophages in various human and mouse atherosclerotic lesions were investigated by immunohistochemical examination and quantitative real-time polymerase chain reaction. Histamine is expressed in atherosclerosis, and it induces inflammation and immunity. Human- and mice-derived monocytes and macrophages were used to examine the role of histamine in macrophage differentiation and CCL22-expression. Macrophages derived from histamine receptor 1 (H1R)- and 2 (H2R)-knockout (KO) mice were also examined.Results: Atherosclerotic lesions showed a distribution of heterogeneous macrophage phenotypes with M1-like and M2-like macrophage dominant sites. CCL22 was distributed in sparse areas of vascular smooth muscle cells (VSMCs) and associated with M2-like macrophages. Moreover, H2R stimulation was associated with CCL22 expression via M2-like macrophage dominant differentiation.Conclusion: The expression of M1- or M2-like macrophages in atherosclerosis were observed to be dependent on the distribution of VSMCs owing to differences in causal stimuli and the switching of histamine receptors via Th1 or Th2 cytokines. These results suggest that CCL22 may control atherosclerosis.

Macrophage CCL22 expression in the tumor microenvironment and implications for survival in patients with squamous cell carcinoma of the tongue

“…Some of the CD68‐positive macrophages were also CCL22‐positive (data not shown). CCL22 and CD163 were expressed in the same macrophages (Figure D), as reported previously …”

“…CCL22 is known to be involved in the migration of Th2 cells and Tregs via CCR4 . When Th2 cells accumulate in the periphery of the tumor, the surrounding tumor microenvironment is dominated by Th2 cytokines, such as IL‐4, thereby promoting the differentiation of TAMs into M2‐like macrophages . An increase in this positive mechanism further increases the number of CD163‐positive TAMs surrounding the tumor and promotes lymphatic vessel invasion …”

“…Th2 cytokines, such as IL-4, 13 thereby promoting the differentiation of TAMs into M2-like macrophages. 28 An increase in this positive mechanism further increases the number of CD163-positive TAMs surrounding the tumor and promotes lymphatic vessel invasion.…”

“…CCL22, mainly synthesized by M2‐like macrophages, is a member of the CC chemokine subfamily; its receptor is CCR4, also known as a molecular target in cancer immunotherapy . In a previous study, we showed that CCL22 is expressed on CD163‐positive macrophages via Th2 cells by activating CCR4 …”

“…12 In a previous study, we showed that CCL22 is expressed on CD163-positive macrophages via Th2 cells by activating CCR4. 13 Among the various conventional grading systems used for the assessment of OSCC tissues (including the worst pattern of invasion [WPOI]), 14 the Yamamoto-Kohama (YK) mode of invasion 15 has been associated with prognosis. 16 The YK mode of invasion was derived from the grading of the mode of invasion originally described by Jacobson,et al 17 ; in this histological grading, grade 4 is sub-classed into grades 4C and 4D, whereas the evaluation of other grades is the same as defined by Jacobson's classification.…”