Blocking MAPK Signaling Downregulates CCL21 in Lymphatic Endothelial Cells and Impairs Contact Hypersensitivity Responses

Abstract

CCL21 expression by lymphatic endothelial cells (LECs) is essential for migration of CCR7+ immune cells from skin to regional lymph nodes (LNs). We investigated the importance of mitogen-activated protein kinase (MAPK) signaling in CCL21 expression by ECs in vitro and in vivo. Normal human dermal lymphatic microvascular ECs (HMVEC-dLy) stimulated in vitro with oncostatin M (OSM) expressed high amounts of CCL21 mRNA. CCL21 protein expression by HMVEC-dLy was also markedly increased by OSM compared with unstimulated cultures. Marked phosphorylation of MAPK 44/42 was detected in HMVEC-dLy stimulated by OSM. CCL21 expression by HMVEC-dLy was blocked by a JAK inhibitor 1, JAK3 inhibitor, and U0126 (a MAPK kinase inhibitor) in vitro, all of which blocked phosphorylation of MAPK 44/42. In addition, injection of U0126 into murine skin significantly decreased CCL21 mRNA and protein expression. Moreover, injection of U0126 before sensitization decreased migration of dendritic cells to draining LNs and decreased contact hypersensitivity responses. In summary, these results suggest that the MAPK pathway is important for CCL21 expression by LECs in vitro and in vivo. Blocking MAPK signaling within skin may offer a novel approach to treatment of inflammatory skin diseases.

Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma

“…Migration into secondary lymphoid tissue could be another explanation for the loss of peripheral CD4 + cells observed in our study. CCL21 is a major chemoattractant for CD4 + T cells [16]. Since activation of the MAPK pathway results in increased secretion of CCL21 by lymphatic endothelial cells [16], vemurafenib could induce migration into secondary lymphoid organs, but the effect of vemurafenib on endothelial cells remains to be determined.…”

“…CCL21 is a major chemoattractant for CD4 + T cells [16]. Since activation of the MAPK pathway results in increased secretion of CCL21 by lymphatic endothelial cells [16], vemurafenib could induce migration into secondary lymphoid organs, but the effect of vemurafenib on endothelial cells remains to be determined. The decline in circulating CD4 + T cells appears not to be due to decreased survival but to a change in the compartmental distribution of CD4 + T cells.…”

Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

“…In addition to NF-κB, STAT1 and STAT2 have been shown to transcriptionally regulate CCL19 [113], and STAT3 transcriptionally regulates CCL21 [121]. STAT (Signal transducer and activators of transcription) molecules are extremely diverse in their function.…”

New Insights of CCR7 Signaling in Dendritic Cell Migration and Inflammatory Diseases

“…Roxatidine, used to treat gastric and duodenal ulcers, can suppress the accumulation of DCs in dLNs in chemical allergen-induced contact hypersensitivity, which may also be by the mechanism of attenuated MAPK signal (Lee et al, 2017). Moreover, inhibition of MEK, the upstream molecules of ERK, by U0126 and PD184352, can effectively ease contact hypersensitivity responses and rheumatoid arthritis (Thiel et al, 2007;Miyagaki et al, 2011). However, whether they function through DCs directly remains to be investigated.…”