IL-17A Induces Endothelial Inflammation in Systemic Sclerosis via the ERK Signaling Pathway

Xing, Xiaojing; Yang, Ji; Yang, Xi-shan; Wei, Yi; Zhu, Liangliang; Gao, Di; Li, Ming

doi:10.1371/journal.pone.0085032

Cited by 77 publications

(61 citation statements)

References 35 publications

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“…On the other hand, human lung microvascular ECs do appear to express IL-17RA and respond to IL-17 activation, although the magnitude of the responses observed while comparable to TNF in this cell type, are quite weak by comparisons to TNF responses in other studies (26, 27). It has also been reported that HUVECs expressed CCL20 and adhesion molecules (ICAM-1 and VCAM-1) after IL-17 stimulation, but the magnitude of expression observed in this study was again very limited (28). These data cumulatively suggest that while some EC types may respond to IL-17, the magnitude of the human EC response is very small and unlikely to account for the powerful role that IL-17 exhibits in neutrophilic inflammation.…”

Section: Discussionsupporting

confidence: 42%

IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium

Liu

Lauridsen

Amezquita

et al. 2016

The Journal of Immunology

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A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multi-step process that involves sequential cell-cell interactions of circulating leukocytes with interleukin (IL)-1- or tumor necrosis factor-α (TNF)-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a pro-inflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, while neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA-seq analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media (CM) from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and also stimulate neutrophil production of pro-inflammatory molecules, including TNF, IL-1α, IL-1β, and IL-8. Furthermore, IL-17-activated PCs but not ECs can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondria outer membrane permeabilization and caspase 9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by CM from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space.

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Section: Discussionsupporting

confidence: 42%

IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium

Liu

Lauridsen

Amezquita

et al. 2016

The Journal of Immunology

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“…Besides its direct effects on G-CSF-mediated mobilization of neutrophils from the bone marrow, IL-17A may also contribute to neutrophil homing to the kidney by stimulating expression of adhesion molecules (e.g. VCAM-1 and E-Selectin) on the renal endothelium 77,78 . While under steady state conditions, phagocytosis of neutrophils downregulates IL-23 and subsequently IL-17-triggered neutrophil recruitment, 70 the upstream pathways that regulate IL-17A expression in response to UV light are yet to be defined.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Skopelja-Gardner

Tai

Sun

et al. 2020

Preprint

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Photosensitivity to ultraviolet (UV) light affects up to ~80% of lupus patients and can exacerbate local skin disease as well as systemic disease, including lupus nephritis. While neutrophils have been implicated in local tissue injury in lupus in response to immune complex deposition, whether and how they play a role in photosensitivity induced systemic disease is unknown. Here, we show that following skin exposure to UV light, neutrophils migrate not only to the skin, but also to the kidney, in an IL-17A-dependent manner. Kidney infiltrating neutrophils produced reactive oxygen species and their presence was associated with upregulation of endothelial adhesion molecules and inflammatory cytokines as well as the induction of kidney injury markers, including transient proteinuria. Neutrophils were responsible for inflammation and renal injury as demonstrated by experiments that inhibited neutrophil mobilization. Exploiting a mouse model containing photoactivatable immune cells, we observed that a subset of neutrophils found in the kidney had transited through UV light-exposed skin suggesting reverse transmigration. These findings demonstrate that neutrophils mediate transient kidney injury following skin exposure to UV light and, coupled with observations identifying similar neutrophil phenotypes in human lupus, could provide a mechanistic link to explain sun-induced systemic lupus flares.

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“…Both insulin and IGF1 have been found to induce VCAM-1 expression in the vascular endothelial cells [23,24]. IL-17 can also increase expression of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), VCAM-1 and E-selectin in the endothelial cells [25,26]. It has been shown that insulin can augment tumor necrosis factor-a (TNF-a)-induced expression of VCAM-1 in the endothelial cells [27].…”

Section: Introductionmentioning

confidence: 99%

IL‐17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through CD44‐VCAM‐1 interaction

et al. 2015

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BACKGROUND Extravasation is a critical step in cancer metastasis, in which adhesion of intravascular cancer cells to the vascular endothelial cells is controlled by cell surface adhesion molecules. The role of interleukin-17 (IL-17), insulin, and insulin-like growth factor 1 (IGF1) in adhesion of prostate cancer cells to the vascular endothelial cells is unknown, which is the subject of the present study. METHODS Human umbilical vein endothelial cells (HUVECs) and human prostate cancer cell lines (PC-3, DU-145, LNCaP, and C4-2B) were analyzed for expression of vascular cell adhesion molecule 1 (VCAM-1), integrins, and cluster of differentiation 44 (CD44) using flow cytometry and Western blot analysis. The effects of IL-17, insulin and IGF1 on VCAM-1 expression and adhesion of prostate cancer cells to HUVECs were examined. The interaction of VCAM-1 and CD44 was assessed using immunoprecipitation assays. RESULTS Insulin and IGF1 acted with IL-17 to increase VCAM-1 expression in HUVECs. PC-3, DU-145, LNCaP, and C4-2B cells expressed β1 integrin but not α4 integrin. CD44 was expressed by PC-3 and DU-145 cells but not by LNCaP or C4-2B cells. When HUVECs were treated with IL-17, insulin or IGF1, particularly with a combination of IL-17 and insulin (or IGF1), adhesion of PC-3 and DU-145 cells to HUVECs was significantly increased. In contrast, adhesion of LNCaP and C4-2B cells to HUVECs was not affected by treatment of HUVECs with IL-17 and/or insulin/IGF1. CD44 expressed in PC-3 cells physically bound to VCAM-1 expressed in HUVECs. CONCLUSIONS CD44-VCAM-1 interaction mediates the adhesion between prostate cancer cells and HUVECs. IL-17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through increasing VCAM-1 expression in the vascular endothelial cells. These findings suggest that IL-17 may act with insulin/IGF1 to promote prostate cancer metastasis.

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IL-17A Induces Endothelial Inflammation in Systemic Sclerosis via the ERK Signaling Pathway

Cited by 77 publications

References 35 publications

IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium

IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

IL‐17 and insulin/IGF1 enhance adhesion of prostate cancer cells to vascular endothelial cells through CD44‐VCAM‐1 interaction

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