CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation

Abstract

Microglia, resident macrophages in the brain, play major roles in neuroinflammation after an acute many neurological diseases, including stroke. Our recent animal stroke model showed that interleukin (IL)-4 and IL-13 released by microglia are converted into monocyte-derived macrophages. However, the correlation with the migration mechanism of these cells is still unclear. This study aimed to clarify the effect of these cells on their migration and to identify potential targets that influence neuroinflammatory conditions. Inflammatory conditions were induced by lipopolysaccharide (LPS) treatment in in vitro and in vivo models. Cell migration was observed using transwell assay, and target chemokines were screened using the proteome profiler array in the in vitro model. Intravital, IVIS, and CLARITY imaging were used in the in vivo model. After LPS (1 ng/ml) treatment in BV2 (microglia cell line) and J774 (monocyte/macrophage cell line) cells, BV2 migration was approximately two-fold more enhanced compared to J774 migration. Overall, six types of chemokine C-C motif ligands (CCLs) were detected from the BV2 conditioned medium with LPS. These CCLs were related to C-C motif receptor (CCR)4 and CCR5. In the in vivo model, CCR4 and CCR5 antagonist significantly inhibited the migration of monocyte-derived macrophages to brain tissue following LPS (5 µg) treatment. In conclusion, the chemokines released by microglia may influence migration of monocyte-derived macrophages in necroinflammation conditions inducted by microglial activation. CCR4 and CCR5 expressed on monocyte-derived macrophages interacted with these chemokines and induced migration. Therefore, CCR4 and CCR5 may be explored as new therapeutic targets for neuroinflammation.

Monocyte‐related cytokines/chemokines in cerebral ischemic stroke

“…CCR5 mediates MDM migration, and its inhibition has been shown to suppress the migration of MDMs to the brain parenchyma in an in vivo model. 74 CCR5 and its ligand, CCL5, are involved in the pathology of ischemic stroke and monocyte recruitment. CCL5/CCR5 expression increases in the ischemic hemisphere.…”

“…CCR5 is mainly expressed on the surface of intermediate monocytes. CCR5 mediates MDM migration, and its inhibition has been shown to suppress the migration of MDMs to the brain parenchyma in an in vivo model 74 …”

Role of macrophages in pulmonary arterial hypertension

“…Although macrophage uptake of lipoproteins appears to be beneficial, these "foam cells" exacerbate disease by secreting proinflammatory mediators, including cytokines and ROS, and ultimately leading to death through necrosis or apoptosis. Studies have shown that CCR4 shows a more obvious M2 activation, as demonstrated by the elevated representation of the archetypal M2 markers ARG1 and FIZZ1 (132)(133)(134). Chemokine C-X-C motif ligand 4 (CXCL4/PF-4), a platelet-derived chemokine (135,136), has been shown to prevent monocyte apoptosis and promote macrophage differentiation in vitro (137).…”

Neuroinflammatory response on a newly combinatorial cell–cell interaction chip

“…[1][2][3] Therefore, visually capturing and analyzing biological indicators associated with neuroinflammation, such as immune cell-derived cytokines, cell migratory behaviors, etc., will ultimately enhance the understanding of pathological processes. 4,5 Animal models and in vitro 2D cell models for neuroinflammation-related diseases have already provided some important information. However, animal models face ethical concerns, high costs, and species differences in efflux transporters, tight junctions, and cell-cell signaling.…”

“…1–3 Therefore, visually capturing and analyzing biological indicators associated with neuroinflammation, such as immune cell-derived cytokines, cell migratory behaviors, etc ., will ultimately enhance the understanding of pathological processes. 4,5…”