Epigenetic regulation of CC-chemokine ligand 2 in nonresolving inflammation

Abstract

Inflammation mediated by the crosstalk between leukocytes and resident tissue cells is crucial for the maintenance of homeostasis. Because chemokine ligands and receptors, which recruit a variety of leukocytes, are widely distributed among tissues, it is important to understand the mechanisms regulating inflammatory disease. Chemokines such as CC-chemokine ligand 2 (CCL2) amplify and maintain inflammation through chemokine-cytokine networks after the recruitment of circulating leukocytes. Chemokine-dependent nonresolving inflammation occurs in the peripheral and central nervous systems, and underlies several intractable diseases, including cancer and neuropathic pain. The chronic upregulation of chemokines is often mediated by epigenetic mechanisms consisting of DNA methylation, histone modification, and nucleosome positioning. In particular, histone acetylation and methylation have been shown to play important roles in the upregulation of chemokine expression. In addition to CCL2, several other chemokines strongly contribute to neuropathic pain through epigenetic induction. Consequently, targeting epigenetic changes may have therapeutic potential for nonresolving inflammatory diseases such as neuropathic pain. Further research into the epigenetics of inflammatory diseases should promote the development of novel and effective treatment strategies for intractable inflammatory diseases.

Syndecan‐1 regulates dendritic cell migration in cutaneous hypersensitivity to haptens

“…[14] CCL2 amplify and maintain inflammation through chemokine-cytokine networks after the recruitment of circulating leucocytes. [22] In our study, the time-dependent upregulation of CCL2 and CCL3 during SDC1−/− DC maturation may also be account for increased recruitment of leucocytes explaining the observed increased cellular infiltrate in the CHS reaction in SDC1−/− mice (Figure 2A).…”

Dying to Be Noticed: Epigenetic Regulation of Immunogenic Cell Death for Cancer Immunotherapy

“…This pathway has been shown to evoke ICD in melanoma, acute-promyelocytic leukemia, and pancreatic cancer models ( 31 ). Most recently, this concept has been shown to be important in neutrophil-based anticancer activity, where apoptotic cancer cells release epigenetically regulated cytokines such as CXCL1, CXCL10, and CCL2, driving nucleic acid-elicited phagocytosis of dying cancer cells by neutrophils ( 13 , 110 , 111 ).…”

Pharmacological Regulation of Neuropathic Pain Driven by Inflammatory Macrophages

“…These molecules recruit circulating leukocytes into the inflamed tissue and activate various cell types via engagement of cell surface receptors [ 69 , 120 ]. Of the four chemokine families, CC-chemokines are the most well-established regulators of neuropathic pain [ 30 , 121 , 122 , 123 ]. In particular, many studies have demonstrated that CCL2 is upregulated in macrophages and damaged Schwann cells following nerve injury [ 26 , 51 , 124 , 125 ], and pharmacological or genetic inhibition of CCL2 and/or its receptor CCR2 markedly alleviates neuropathic pain [ 126 , 127 , 128 ].…”

“…Recently, CCL3 (macrophage inflammatory protein-1α, MIP-1α) and CCL4 (MIP-1β) have been shown to be upregulated in macrophages and Schwann cells following nerve injury, and to play critical roles in orchestrating long-lasting neuroinflammation in the peripheral nervous system [ 23 , 30 , 123 , 129 ]. Because their receptors (CCR1 and CCR5) are also expressed on macrophages and Schwann cells, CCL3 and CCL4 can act in an autocrine fashion to drive intracellular signaling for upregulation of inflammatory molecules such as IL-1β.…”