Involvement of the CXCL12/CXCR4 Pathway in the Recovery of Skin Following Burns

Avniel, Shani; Zaretski, Arik; Maly, Alex; Sagie, Assa; Basst, Hanna Ben; Yahana, Merav Darash; Weiss, Ido D.; Pal, Boaz; Wald, Ori; Ad‐El, Dean; Fujii, Nobutaka; Arenzana-Seisdedos, Fernando; Jung, Steffen; Galun, Eithan; Gur, Eyal; Peled, Amnon

doi:10.1038/sj.jid.5700069

Cited by 123 publications

(116 citation statements)

References 32 publications

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“…In our study, we have used fibroblasts as a general source of CXCL12. However, it should be noted that other dermis-derived cells also secrete CXCL12 [21][22][23][24][25] and therefore our findings may not be restricted to just fibroblasts, but may involve dermisderived stromal cells in general. We propose that dermis-derived cells play a role in creating a directional chemotactic gradient between the epidermis and the dermis, by secreting chemokines in response to epidermis-derived cytokines (e.g.…”

Section: Discussionmentioning

confidence: 90%

“…Fibroblasts are known to secrete many chemokines. Recently, it was shown that the constitutive chemokine CXCL12 is also secreted by fibroblasts and its secretion is enhanced upon exposure to stress factors, such as hypoxia, irradiation, and burns [21][22][23][24][25]. CXCL12 secretion is not restricted to fibroblasts though, since endothelial cells and DC are also located in the dermis and also secrete CXCL12 [23,26,27].…”

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confidence: 99%

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CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

et al. 2008

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The initial step in Langerhans cell (LC) migration from the epidermis to the lymph node involves migration of maturing LC into the dermis. Here, we investigated the migration of LC out of the epidermis after exposure of the skin to contact allergens. Ex vivo intact human skin, epidermal sheets, and LC derived from the MUTZ-3 cell line (MUTZ-LC) were used to determine whether dermal fibroblasts play a role in mediating LC migration towards the dermis. Exposure of epidermal sheets or MUTZ-LC to allergens (nickel sulphate, 2,4-dinitrochlorobenzene, and cinnamaldehyde) or a cytokine maturation cocktail resulted in LC migration towards dermal fibroblasts. This was due to upregulation of CXCR4 on maturing LC and secretion of CXCL12/stromal derived factor-1 chemokine by fibroblasts. Neutralizing antibodies to either CXCL12 or CXCR4 completely blocked migration. Injection of CXCL12 neutralizing antibodies into intact human skin totally inhibited LC migration into the dermis. In contrast, neutralizing antibodies to CCL19/ CCL21 did not inhibit migration into the dermis. We describe a novel and essential role of dermis-derived CXCL12 in initiating migration of maturing human LC to the dermis thus permitting their further journey to the draining lymph nodes.Key words: Allergy . Chemotaxis . Cytokines . DC . Skin See accompanying commentary by Villablanca and Rodrigo IntroductionHuman skin is the external barrier to harmful environmental factors. Upon environmental assault (e.g. exposure to pathogens or allergens), Langerhans cells (LC) residing in the epidermis start to mature and migrate through the dermis [1,2]. Pathogenor allergen-exposed LC then migrate further into the afferent lymphatics towards the local lymph node where they are able to initiate a T-cell-mediated response [3]. LC migration is regulated by the sequential and differential expression of chemokines and their receptors [4,5]. Although migration to the lymph node is well documented, the chemokine ligands/receptors involved in the initial step of human LC migration out of the epidermis and into the dermis are as yet unknown.Several studies describe an essential role of CCR7 in mediating migration of mature LC towards the lymphatics [6][7][8][9][10]. CCR7 is highly expressed on fully mature, but not on immature LC, and is the chemokine receptor for the ligands CCL19 (MIP-3b) and CCL21 (6Ckine) [11][12][13]. Both of these chemokines are upregulated by lymphatic endothelial cells in response to allergen exposure [14]. Simultaneously, the chemokine receptor CCR6 on LC is downregulated upon maturation [15]. CCR6 is the receptor for CCL20 , which is mainly produced by keratinocytes (KC) in clinically normal human skin. CCR6/CCL20 is thought to 3050be of importance for epidermal homeostasis and homing of immature LC [16][17][18][19]. Taken together these reports show that loss of CCR6 and gain of CCR7 play important roles in the migration of mature LC out of the epidermis and into the lymphatic vessels. However, it is probable that other as yet unidentified sig...

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Section: Discussionmentioning

confidence: 90%

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confidence: 99%

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

et al. 2008

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“…The fibroblasts applied in our current study express low but measurable levels of surface CXCR4 and CD74. While no information is yet available about the role of the MIF/ CXCR4 axis in fibroblast migration and wound healing, CXCR4 in conjunction with its cognate ligand SDF-1 (CXCL12) have been implicated in fibroblast migration, both through chemotaxis and chemokinesis, as well as in dermal wound healing responses [39,40]. GPCR-mediated cell migratory responses lead to a rise in intracellular calcium as part of the signalling process and MIF-triggered leukocyte migration involves calcium signalling [11].…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch‐wounded monolayers in vitro

Dewor

Steffens²,

Krohn³

et al. 2007

FEBS Letters

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MIF was recently redefined as an inflammatory cytokine, which functions as a critical mediator of diseases such as septic shock, rheumatoid arthritis, atherosclerosis, and cancer. MIF also regulates wound healing processes. Given that fibroblast migration is a central event in wound healing and that MIF was recently demonstrated to promote leukocyte migration through an interaction with G-protein-coupled receptors, we investigated the effect of MIF on fibroblast migration in wounded monolayers in vitro. Transient but not permanent exposure of primary mouse or human fibroblasts with MIF significantly promoted wound closure, a response that encompassed both a proliferative and a pro-migratory component. Importantly, MIF-induced fibroblast activation was accompanied by an induction of calcium signalling, whereas chronic exposure with MIF down-regulated the calcium transient, suggesting receptor desensitization as the underlying mechanism.

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“…3-Amino-9-ethylcarbazole was used for color development and sections were counterstained with hematoxylin. As negative controls, sections were stained either with no primary Ab (PBS) or with an isotype-matched control Ab (24,25).…”

Section: Immunohistochemistrymentioning

confidence: 99%

CD4+CXCR4highCD69+ T Cells Accumulate in Lung Adenocarcinoma

Wald¹,

Izhar

Amir³

et al. 2006

The Journal of Immunology

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The chemokine receptor CXCR4 is involved in the growth and metastasis of tumor cells. However, the expression of its ligand, the chemokine CXCL12, in tumors and its role in regulating the accumulation of immune cells within the tumors is not clear. Using ELISA and immunohistochemistry we found that CXCL12 is expressed in the majority of nonsmall cell lung cancer tissue sections obtained from stage IA to IIB nonsmall cell lung cancer patients undergoing operation. Histopathologic examination of these sections indicated that high CXCL12 expression correlated with increased tumor inflammation. In addition, disease recurrence rates in a subgroup of adenocarcinoma patients showed a tendency to correlate with high CXCL12 expression in the tumor. Isolation of adenocarcinoma-infiltrating immune cells demonstrated an increase in the percentage of CD4+CD69+CXCR4+ T cells as compared with normal lung tissue. About 30% of these cells expressed the regulatory T cell markers CD25high and FoxP3. The percentage of CD8 T cells within the tumor did not change, however; the percentage of NK and NK T cells was significantly reduced. In correlation with CXCR4 expression, CD4 T cells showed increased migration in response to CXCL12 compared with CD8 T cells and NK cells. Overall, these observations suggest that CXCL12 expression may influence tumor progression by shaping the immune cell population infiltrating lung adenocarcinoma tumors.

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Involvement of the CXCL12/CXCR4 Pathway in the Recovery of Skin Following Burns

Cited by 123 publications

References 32 publications

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch‐wounded monolayers in vitro

CD4+CXCR4highCD69+ T Cells Accumulate in Lung Adenocarcinoma

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