CCL22-specific Antibodies Reveal That Engagement of Two Distinct Binding Domains on CCL22 Is Required for CCR4-mediated Function

Santulli-Marotto, Sandra; Wheeler, J. C.; Lacy, Eilyn R.; Boakye, Ken; Luongo, Jennifer L.; Wu, Sheng‐Jiun; Ryan, Mary

doi:10.1089/mab.2015.0039

Cited by 5 publications

(1 citation statement)

References 38 publications

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“…CCL22 was unable to induce pain, at least at the doses tested. This result is perhaps surprising, as it is widely considered that both of these chemokines share CCR4 as a common receptor (43,56,57). However, despite CCL17 and CCL22 both binding to CCR4, they are conformationally selective ligands of CCR4 and interact with it by substantially different mechanisms (43,56,57).…”

Section: Discussionmentioning

confidence: 99%

CCL17 in Inflammation and Pain

Lee

Jarnicki

Achuthan

et al. 2020

The Journal of Immunology

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It has been reported that a GM-CSF→CCL17 pathway, originally identified in vitro in macrophage lineage populations, is implicated in the control of inflammatory pain, as well as arthritic pain and disease. We explore, in this study and in various inflammation models, the cellular CCL17 expression and its GM-CSF dependence as well as the function of CCL17 in inflammation and pain. This study used models allowing the convenient cell isolation from Ccl17 E/+ reporter mice; it also exploited both CCL17-dependent and unique CCL17-driven inflammatory pain and arthritis models, the latter permitting a radiation chimera approach to help identify the CCL17 responding cell type(s) and the mediators downstream of CCL17 in the control of inflammation and pain. We present evidence that 1) in the particular inflammation models studied, CCL17 expression is predominantly in macrophage lineage populations and is GM-CSF dependent, 2) for its action in arthritic pain and disease development, CCL17 acts on CCR4 + non-bone marrow-derived cells, and 3) for inflammatory pain development in which a GM-CSF→CCL17 pathway appears critical, nerve growth factor, CGRP, and substance P all appear to be required.

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Section: Discussionmentioning

confidence: 99%

CCL17 in Inflammation and Pain

Lee

Jarnicki

Achuthan

et al. 2020

The Journal of Immunology

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Chemokine neutralization as an innovative therapeutic strategy for atopic dermatitis

Abboud

Hanson

2017

Drug Discovery Today

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Downstream STING pathways IRF3 and NF-κB differentially regulate CCL22 in response to cytosolic dsDNA

Kim,

Pena,

McQueen

et al. 2023

Cancer Gene Ther

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Double-stranded DNA (dsDNA) in the cytoplasm of eukaryotic cells is abnormal and typically indicates the presence of pathogens or mislocalized self-DNA. Multiple sensors detect cytosolic dsDNA and trigger robust immune responses via activation of type I interferons. Several cancer immunotherapy treatments also activate cytosolic nucleic acid sensing pathways, including oncolytic viruses, nucleic acid-based cancer vaccines, and pharmacological agonists. We report here that cytosolic dsDNA introduced into malignant cells can robustly upregulate expression of CCL22, a chemokine responsible for the recruitment of regulatory T cells (Tregs). Tregs in the tumor microenvironment are thought to repress antitumor immune responses and contribute to tumor immune evasion. Surprisingly, we found that CCL22 upregulation by dsDNA was mediated primarily by interferon regulatory factor 3 (IRF3), a key transcription factor that activates type I interferons. This nding was unexpected given previous reports that type I interferon alpha inhibits CCL22 and that IRF3 is associated with strong anti-tumor immune responses, not Treg recruitment. We also found that CCL22 upregulation by dsDNA occurred concurrently with IFN-β upregulation. IRF3 is one of two transcription factors downstream of the STimulator of INterferon Genes (STING), which is a hub adaptor protein through which many different dsDNA sensors transmit their signals. The other transcription factor downstream of STING, NF-κB, has been reported to regulate CCL22 expression in other contexts, and NF-κB has been ascribed multiple pro-tumor functions, including Treg recruitment. However, we found that NF-κB in the context of activation by cytosolic dsDNA contributed minimally to CCL22 upregulation compared with IRF3. Lastly, we observed that two strains of the same cell line differed profoundly in their capacity to upregulate CCL22 and IFN-β in response to dsDNA, despite apparent STING activation in both cell lines. This nding suggests that during tumor evolution, cells can acquire, or lose, the ability to upregulate CCL22. This study adds to our understanding of factors that may modulate immune activation in response to cytosolic DNA and has implications for immunotherapy strategies that activate DNA sensing pathways in cancer cells.

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CCL22-specific Antibodies Reveal That Engagement of Two Distinct Binding Domains on CCL22 Is Required for CCR4-mediated Function

Cited by 5 publications

References 38 publications

CCL17 in Inflammation and Pain

CCL17 in Inflammation and Pain

Chemokine neutralization as an innovative therapeutic strategy for atopic dermatitis

Downstream STING pathways IRF3 and NF-κB differentially regulate CCL22 in response to cytosolic dsDNA

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