CCL2 nitration is a negative regulator of chemokine-mediated inflammation

Barker, Catrin; Thompson, Sarah; O'Boyle, Graeme; Lortat‐Jacob, Hugues; Sheerin, Neil; Ali, Simi; Kirby, John A.

doi:10.1038/srep44384

Cited by 29 publications

(35 citation statements)

References 42 publications

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“…PTMs can be dependent on the cellular source and can alter CCL2's function. For example, nitration of its tyrosine residues by reactive nitrogen species, such as peroxynitrite, has been shown to reduce CCL2-mediated monocyte migration in diffusion gradient chemotaxis and transendothelial migration in Transwell assays (234,235). NO2-CCL2 showed reduced binding to CCR2 and heparan sulfate coreceptors.…”

Section: Can Ccl2 Inhibit Tumor Cell Growth and Enhance Tumor Cell Kimentioning

confidence: 99%

“…NO2-CCL2 showed reduced binding to CCR2 and heparan sulfate coreceptors. In addition, NO2-CCL2 was able to antagonize the effects of unmodified CCL2 in vivo (235). Furthermore, matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to cleave human CCL2 in vitro, which resulted in twofold reduction in THP-1 cell migration (236).…”

Section: Can Ccl2 Inhibit Tumor Cell Growth and Enhance Tumor Cell Kimentioning

confidence: 99%

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More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis

2019

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Monocyte chemoattractant protein-1 (MCP-1/CCL2) is renowned for its ability to drive the chemotaxis of myeloid and lymphoid cells. It orchestrates the migration of these cell types both during physiological immune defense and in pathological circumstances, such as autoimmune diseases including rheumatoid arthritis and multiple sclerosis, inflammatory diseases including atherosclerosis, as well as infectious diseases, obesity, diabetes, and various types of cancer. However, new data suggest that the scope of CCL2's functions may extend beyond its original characterization as a chemoattractant. Emerging evidence shows that it can impact leukocyte behavior, influencing adhesion, polarization, effector molecule secretion, autophagy, killing, and survival. The direction of these CCL2-induced responses is context dependent and, in some cases, synergistic with other inflammatory stimuli. The involvement of CCL2 signaling in multiple diseases renders it an interesting therapeutic target, although current targeting strategies have not met early expectations in the clinic. A better understanding of how CCL2 affects immune cells will be pivotal to the improvement of existing therapeutic approaches and the development of new drugs. Here, we provide an overview of the pleiotropic effects of CCL2 signaling on cells of the myeloid lineage, beyond chemotaxis, and highlight how these actions might help to shape immune cell behavior and tumor immunity.

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Section: Can Ccl2 Inhibit Tumor Cell Growth and Enhance Tumor Cell Kimentioning

confidence: 99%

Section: Can Ccl2 Inhibit Tumor Cell Growth and Enhance Tumor Cell Kimentioning

confidence: 99%

More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis

2019

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“…132,133 Nitrated CCL2 was detected in tissue sections of human prostate and colon carcinoma, and colocalization of CCL2 and nitrotyrosine was found in kidneys after ischemia reperfusion injury. 110,134 As a result of in vitro nitration of CCL2 by peroxynitrite, Molon et al 110 observed abolished CD8 + T-cell migration and reduced CD14 + monocyte chemotaxis. Other groups also reported reduced monocyte chemotaxis and transendothelial migration following stimulation with nitrated CCL2.…”

Section: Cxcl12 Protein Availability and Cooperativitymentioning

confidence: 99%

“…Other groups also reported reduced monocyte chemotaxis and transendothelial migration following stimulation with nitrated CCL2. 134,135 Remarkably, i.v. administration of nitrated CCL2 inhibited CCL2-mediated recruitment of leukocytes to air pouches in mice, suggesting that nitrated chemokines in circulation aid in the resolution of tissue inflammation.…”

Section: Cxcl12 Protein Availability and Cooperativitymentioning

confidence: 99%

The unique structural and functional features of CXCL12

2017

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The CXC chemokine CXCL12 is an important factor in physiological and pathological processes, including embryogenesis, hematopoiesis, angiogenesis and inflammation, because it activates and/or induces migration of hematopoietic progenitor and stem cells, endothelial cells and most leukocytes. Therefore, CXCL12 activity is tightly regulated at multiple levels. CXCL12 has the unique property of existing in six splice variants in humans, each having a specific tissue distribution and in vivo activity. Controlled splice variant transcription and mRNA stability determine the CXCL12 expression profile. CXCL12 fulfills its functions in homeostatic and pathological conditions by interacting with its receptors CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) and by binding to glycosaminoglycans (GAGs) in tissues and on the endothelium to allow a proper presentation to passing leukocytes. Homodimerizaton and heterodimerization of CXCL12 and its receptors can alter their signaling activity, as exemplified by the synergy between CXCL12 and other chemokines in leukocyte migration assays. Receptor binding may also initiate CXCL12 internalization and its subsequent removal from the environment. Furthermore, CXCL12 activity is regulated by posttranslational modifications. Proteolytic removal of NH- or COOH-terminal amino acids, citrullination of arginine residues by peptidyl arginine deiminases or nitration of tyrosine residues reduce CXCL12 activity. This review summarizes the interactions of CXCL12 with the cellular environment and discusses the different levels of CXCL12 activity regulation.

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“…Although these modifications mostly lead to changes in receptor activity, also GAG-binding affinity can be altered. Recently, nitrated CCL2 with reduced in vitro and in vivo activity was described (208). This could be partially attributed to reduced GAG binding of the nitrated chemokine.…”

Section: Consequences Of Ccl2 Ccl7 Ccl8 and Ccl13 Binding To Glycomentioning

confidence: 99%

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

2020

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Leukocyte migration into tissues depends on the activity of chemokines that form concentration gradients to guide leukocytes to a specific site. Interaction of chemokines with their specific G protein-coupled receptors (GPCRs) on leukocytes induces leukocyte adhesion to the endothelial cells, followed by extravasation of the leukocytes and subsequent directed migration along the chemotactic gradient. Interaction of chemokines with glycosaminoglycans (GAGs) is crucial for extravasation in vivo. Chemokines need to interact with GAGs on endothelial cells and in the extracellular matrix in tissues in order to be presented on the endothelium of blood vessels and to create a concentration gradient. Local chemokine retention establishes a chemokine gradient and prevents diffusion and degradation. During the last two decades, research aiming at reducing chemokine activity mainly focused on the identification of inhibitors of the interaction between chemokines and their cognate GPCRs. This approach only resulted in limited success. However, an alternative strategy, targeting chemokine-GAG interactions, may be a promising approach to inhibit chemokine activity and inflammation. On this line, proteins derived from viruses and parasites that bind chemokines or GAGs may have the potential to interfere with chemokine-GAG interactions. Alternatively, chemokine mimetics, including truncated chemokines and mutant chemokines, can compete with chemokines for binding to GAGs. Such truncated or mutated chemokines are characterized by a strong binding affinity for GAGs and abrogated binding to their chemokine receptors. Finally, Spiegelmers that mask the GAG-binding site on chemokines, thereby preventing chemokine-GAG interactions, were developed. In this review, the importance of GAGs for chemokine activity in vivo and strategies that could be employed to target chemokine-GAG interactions will be discussed in the context of inflammation.

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CCL2 nitration is a negative regulator of chemokine-mediated inflammation

Cited by 29 publications

References 42 publications

More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis

More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis

The unique structural and functional features of CXCL12

Targeting Chemokine—Glycosaminoglycan Interactions to Inhibit Inflammation

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