CCL2/CCR chemokine

Introduction

CCL2 is the monocyte chemokine C-C motif ligand (CCL) 2
- also called small inducible cytokine A2
CCL2 is a member of the CC chemokine superfamily, which binds to its receptor, C-C motif chemokine receptor-2 (CCR2), for the induction of chemotactic activity and an increase of calcium influx to induce monocyte infiltration and mediate inflammation
it exerts multiple effects on a variety of cells, including monocytes, macrophages, osteoclasts, basophils, and endothelial cells, and is involved in a diverse range of diseases
in the brain it is produced by neurons and glial cells
- the CCL2/CCR2 signaling pathway participates in the transduction of neuroinflammatory information between all types of cells in the central nervous system
in the skeletal system, the expression of CCL2 is regulated by a variety of factors, such as parathyroid hormone/parathyroid hormone-related peptide, interleukin 1b, tumor necrosis factor-α and transforming growth factor-beta, RANKL, and mechanical forces. ¹⁾
the interaction of CCL2 and CCR2 activates several signaling cascades, including PI3K/Akt/ERK/NF-κB, PI3K/MAPKs, and JAK/STAT-1/STAT-3 ²⁾
the CCL2/CCR2 axis plays a significant role in ageing, cachexia, the pathogenesis of cardiovascular lesions, type 1 and type 2 diabetes mellitus, oncogenesis, and complications associated with atherosclerosis, including ischaemic stroke, myocardial infarction, acute coronary syndrome, and severe heart failure

in cancer patients, cancer induced systemic inflammation causes over-expression of CCL2 in the brain and this results in dysregulation of vagal activity, lower vagal tone and resulting cachexia via impaired hepatic protein synthesis

CCL2/CCR2 mediate the pathological process of ischaemic stroke, and a higher CCL2 level in serum is associated with a higher risk of any form of stroke
in the acute phase of cerebral ischaemia-reperfusion, the expression of CCL2/CCR2 is increased in the ischaemic penumbra, which promotes neuroinflammation and enhances brain injury. In the later phase, it participates in the migration of neuroblasts to the ischemic area and promotes the recovery of neurological function. CCL2/CCR2 gene knockout or activity inhibition can reduce the nerve inflammation and brain injury induced by cerebral ischemia-reperfusion. ³⁾

CCL2-CCR2 signaling promotes hepatic ischemia/reperfusion (I/R) injury - Kupffer cells secrete CCL2 to promote CCR2-expressing neutrophil recruitment from the bone marrow and subsequent infiltration into the liver during I/R. ⁴⁾

besides the chemotactic activity, the CCL2-CCR2 axis is involved in various neurobiological processes, neurogenesis, neurotransmission, neuroinflammation, neurodegeneration, as well as neuroregeneration.⁵⁾
CCL2 plays a key role in the transmigration of leucocytes across the blood–brain barrier (BBB), CCL2 is consumed by migrating inflammatory cells, which downregulate CCR2, as they cross the BBB, CCL2 levels are consistently decreased in the CSF of multiple sclerosis (MS) patients and other chronic neuroinflammatory conditions, despite abundant expression within lesional multiple sclerosis tissues ⁶⁾
neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection⁷⁾
has been implicated in Alzheimer's Disease
- overexpression of CCL2 in the CNS contributes to an increase in pathogenic types of tau protein and is associated with glial neuroinflammatory changes
- CCL2 and CCR2 are involved in altered amyloid beta (Aβ) metabolism which underlies Alzheimer’s disease
has been implicated in depression
has been implicated in the cognitive decline of ageing ⁸⁾