Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

Figures

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  Figure 1. Adipose tissue cells secrete distinct adipokines. Adipose tissue consists of a variety of cell types, such as adipocytes, preadipocytes, adipose tissue-derived stem cells, and several immune cells which produce and secrete cell-type-specific adipokines. +/−, higher/lower secreted in sc or vis. c-KIT, KIT proto-oncogene, receptor tyrosine kinase; CCL2, C-C motif chemokine ligand 2; CXCL5, C-X-C motif chemokine ligand 5; IFN-γ, interferon-γ; IL, interleukin; PDGF, platelet derived growth factor; RBP4, retinol binding protein 4; SC, subcutaneous; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor; VIS, visceral. Created with BioRender.com.

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  Figure 2. CCL2 signaling. As response to CCL2 binding at the N-terminus, extracellular loops and transmembrane bundle of CCR2, the intracellular G-protein αi subunit dissociates from the CCR2 and the βγ subunit. The α subunit then inhibits adenylyl cyclase (AC) function resulting in decreased cyclic adenosine monophosphate levels. In contrast, the βγ subunit signaling induces gene expression via several pathways. PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; IKK, inhibitor of NF-κB kinase; NF-κB, nuclear factor of kappa-light-chain-enhancer of activated B cells; Ras, rat sarcoma; Rac, ras-related C3 botulinum toxin substrate; Raf, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase; p38, mitogen-activated protein kinase; JNK, c-jun N-terminal kinase; ERK, extracellular signal-regulated kinase; PLC-β, phospholipase C-β; PIP2, phosphatidylinositol 4,5-bisphosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-triphosphate; PKC-β, protein kinase C-β; CAM, Ca2+/calmodulin-dependent protein kinase; c-fos, proto-oncogene c-Fos; c-jun, proto-oncogene Jun; c-myc, proto-oncogene Myc; CREB, cAMP response element-binding protein. Modified from Bose S. & Cho J. [75] using…

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  Figure 3. Effects of CCL2 on different immune cell types. Mono, monocytes; MΦ, macrophages; DC, dendritic cells; FBGCs, foreign body giant cells; MDSC, myeloid-derived suppressor cell; IL-12, interleukin 12; LPS, lipopolysaccharide; CD11b, cluster of differentiation molecule 11B; CD11c, cluster of differentiation molecule 11C. The CCL2 structure was taken from uniprot [86]. Modified from Gschwandtner M. et al. [60] using BioRender.com.

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  Figure 4. CCL2 (red molecules) binds to proteoglycans (blue strands) such as heparan sulfate or heparin, which are part of the extracellular matrix surrounding adipocytes. Whereas lean AT expresses low proteoglycan levels, expression increases with obesity. As coreceptors, proteoglycans immobilize CCL2 and present it to macrophages, resulting in higher AT inflammation (represented by ↑). Modified from Pessentheiner A. et al. [140] using BioRender.com.