The role and therapeutic targeting of the CCL2/CCR2 signaling axis in inflammatory and fibrotic diseases

Abstract

CCL2, a pivotal cytokine within the chemokine family, functions by binding to its receptor CCR2. The CCL2/CCR2 signaling pathway plays a crucial role in the development of fibrosis across multiple organ systems by modulating the recruitment and activation of immune cells, which in turn influences the progression of fibrotic diseases in the liver, intestines, pancreas, heart, lungs, kidneys, and other organs. This paper introduces the biological functions of CCL2 and CCR2, highlighting their similarities and differences concerning fibrotic disorders in various organ systems, and reviews recent progress in the diagnosis and treatment of clinical fibrotic diseases linked to the CCL2/CCR2 signaling pathway. Additionally, further in-depth research is needed to explore the clinical significance of the CCL2/CCR2 axis in fibrotic conditions affecting different organs.

Keywords: CCL2; CCR2; clinical diagnosis and treatment; fibrosis; immune regulation; inflammation.

Figure 1

Schematic diagram of the CCL2/CCR2 axis and its associated signaling pathways. CCR2, a classic G protein-coupled receptor, activates a variety of downstream signaling pathways upon binding to its ligand CCL2, such as PI3K/Akt, JAK/STAT, and P38/MAPK. Activation of these pathways leads to the regulation of various transcription factors and genes involved in cell survival, proliferation, cytokine production, migration, and apoptosis. This figure was created with biogdp.com.

Figure 2

The primary role process of CCL2 in fibrotic diseases. CCL2 facilitates the mobilization of monocytes from the bone marrow into the bloodstream and guides their migration to targeted inflammatory fibrotic areas. Once there, these monocytes differentiate into macrophages to address tissue damage (as exemplified by atherosclerotic plaques), this process is frequently associated with the activation of the NF-κB signaling pathway (as exemplified by systemic mastocytosis). Additionally, the regulation of CCL2 secretion is often influenced by various receptors, which in turn modulate the release of inflammatory mediators (as seen in fibrosis associated with chronic kidney disease). This figure was created with biogdp.com.

Figure 3

Schematic representation of clinical trials for CCL2/CCR2 inhibitors. This figure was created with biogdp.com.

Figure 4

The role of CCL2 in mediating intercellular interactions within fibrotic tissues in various organs. (A). In liver fibrosis, CCL2 plays a critical role by recruiting macrophages to the fibrotic regions and facilitating their M2 polarization, which subsequently activates hepatic stellate cells (HSCs) and promotes collagen deposition. (B). In intestinal fibrosis, Ly6C^hi monocytes are predominant, and an increase in their proportion significantly enhances the expression of CCL2. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) can release IL-10, which facilitates the M2 polarization of intestinal macrophages, subsequently contributing to the development of fibrosis. (C). In pancreatic fibrosis, M2 macrophages secrete pro-fibrotic factors that activate pancreatic stellate cells (PSCs), a process similar to that in liver fibrosis. (D). In lung fibrosis, alveolar epithelial cells (AECs) exhibit increased CCL2 production, facilitating macrophage recruitment to fibrotic regions. Additionally, activated fibroblasts release significant amounts of CCL2 via NF-κB signaling, contributing to collagen accumulation. This figure was created with biogdp.com.