Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasis

Bauer, Thomas; Загорска, Анна; Jurkin, Jennifer; Yasmin, Nighat; Köffel, René; Richter, Susanne; Geßlbauer, Bernhard; Lemke, Greg; Strobl, Herbert

doi:10.1084/jem.20120493

Cited by 102 publications

(103 citation statements)

References 51 publications

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“…1A and leading to MDLCs or MDDCs compared with skin LCs. CD1a and TROP-2 were present on all cell types at day 7 of differentiation whereas Axl was expressed in a TGF-b1-dependent manner as already shown previously (41) (Fig. 4A).…”

Section: Serum Lipids Impair Lc Differentiation Of Monocytes With Tgfsupporting

confidence: 84%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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Langerhans cells (LCs) are epithelial APCs that sense danger signals and in turn trigger specific immune responses. In steady-state, they participate in the maintenance of peripheral tolerance to self-antigens whereas under inflammation LCs efficiently trigger immune responses in secondary lymphoid organs. It has been demonstrated in mice that LC-deprived epithelia are rapidly replenished by short half-life langerin-expressing monocyte-derived LCs (MDLCs). These surrogate LCs are thought to be progressively replaced by langerinhigh LCs arising from self-renewing epithelial precursors of hematopoietic origin. How LCs arise from blood monocytes is not fully understood. Hence, we sought to characterize key factors that induce differentiation of langerinhigh-expressing monocyte-derived Langerhans-like cells. We identified GM-CSF and TGF-β1 as key cytokines to generate langerinhigh-expressing cells but only in serum-free conditions. These cells were shown to express the LC-specific TROP-2 and Axl surface markers and contained Birbeck granules. Surprisingly, E-cadherin was not spontaneously expressed by these cells but required a direct contact with keratinocytes to be stably induced. MDLCs induced stronger allogeneic T cell proliferations but released low amounts of inflammatory cytokines upon TLR stimulation compared with donor-paired monocyte-derived dendritic cells. Immature langerinhigh MDLCs were responsive to MIP-3β/CCL20 and CTAC/CCL27 chemokine stimulations. Finally, we demonstrated that those cells behaved as bona fide LCs when inserted in a three-dimensional rebuilt epithelium by becoming activated upon TLR or UV light stimulations. Collectively, these results prompt us to propose these langerinhigh MDLCs as a relevant model to address LC biology–related questions.

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Section: Serum Lipids Impair Lc Differentiation Of Monocytes With Tgfsupporting

confidence: 84%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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“…To determine whether AXL expression on HUVECs contributed to ZIKV infection, cells were preincubated with an anti-AXL antibody, which blocks Gas6 binding but induces AXL phosphorylation (27,28). ZIKV infection in HUVECs was effectively inhibited by the anti-AXL antibody, but not by control IgG (Fig.…”

Section: Resultsmentioning

confidence: 99%

AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses

Richard

Shim

Kwon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

178

158

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Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXLdependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL.Zika virus | Flaviviruses | AXL | placental barrier | fetal endothelial cell Z ika (ZIKV), West Nile (WNV), and dengue (DENV) viruses are closely related, and belong to the Flavivirus genus in the Flaviviridae family. Although a causal relation between ZIKV and microcephaly has been established by human and animal studies (1-7), it remains unclear why only ZIKV, but not other pathogenic flaviviruses, causes congenital diseases. Although WNV is known to infect neuronal cells and results in encephalitis (8), it does not cause microcephaly. DENV is not generally neurotropic and is not linked to congenital defects.To reach the fetal brain, a virus must be transported from the maternal to the fetal circulation, which necessitates crossing of the placental barrier. In the placenta, fetal blood in capillaries is separated from maternal blood by placental barrier cells, namely trophoblasts and fetal endothelial cells. Recent studies indicate that the placenta and its barrier cells are infected by ZIKV, and fetal brain lesions develop in mice, pigtail macaques, and humans (1-6, 9). However, it remains unclear why only ZIKV, and not other neurotropic flaviviruses, results in microcephaly and other congenital disorders.Although bona fide entry receptors for flaviviruses remain unknown, many cell surface-expressed molecules contribute to infection, including C-type lectins dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and DC-SIGN-related protein (L-SIGN) (10, 11) and phosphatidylserine (PS) receptors (12-15) . PS receptors, which serve as entry cofactors for flaviviruses, include members of the TIM (T-cell Ig mucin) family and the TAM (TYRO3, AXL, and MERTK) family. TIMfamily receptors bind PS directly (14, 15), whereas TAM-family members bind PS indirectly, through the soluble intermediates Gas6 (growth arrest-specific 6) and protein S present in serum and other bodily fluids (16, 17). Whereas Gas6 binds to all th...

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“…TGFβ has been reported to contribute to Axl upregulation during Langerhans cell differentiation(29). Moreover, IL-10 can contribute to Mer upregulation(30).…”

Section: Resultsmentioning

confidence: 99%

TAM Receptor–Dependent Regulation of SOCS3 and MAPKs Contributes to Proinflammatory Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages

Zheng

Hedl

Abraham

2015

The Journal of Immunology

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Microbial-induced cytokine regulation is critical to intestinal immune homeostasis. Acute stimulation of NOD2, the Crohn’s disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, cytokines are attenuated after chronic NOD2 and pattern recognition receptor (PRR) stimulation of macrophages; similar attenuation is observed in intestinal macrophages. The role of Tyro3, Axl and Mer (TAM) receptors in regulating chronic PRR stimulation and NOD2-induced outcomes has not been examined. Moreover, TAM receptors have been relatively less investigated in human macrophages. Whereas TAM receptors did not downregulate acute NOD2-induced cytokines in primary human macrophages, they were essential for downregulating signaling and pro-inflammatory cytokine secretion after chronic NOD2 and TLR4 stimulation. Axl and Mer were similarly required in mice for cytokine downregulation after chronic NOD2 stimulation in vivo and in intestinal tissues. Consistently, TAM expression was increased in human intestinal myeloid-derived cells. Chronic NOD2 stimulation led to IL-10- and TGFβ-dependent TAM upregulation in human macrophages, which in turn, upregulated SOCS3 expression. Restoring SOCS3 expression under TAM knockdown conditions restored chronic NOD2-mediated pro-inflammatory cytokine downregulation. In contrast to the upregulated pro-inflammatory cytokines, attenuated IL-10 secretion was maintained in TAM-deficient macrophages upon chronic NOD2 stimulation. The level of MAPK activation in TAM-deficient macrophages after chronic NOD2 stimulation was insufficient to upregulate IL-10 secretion; however, full restoration of MAPK activation under these conditions restored c-Fos, c-Jun, MAFK and PU.1 binding to the IL-10 promoter and IL-10 secretion. Therefore, TAM receptors are critical for downregulating pro-inflammatory cytokines under the chronic NOD2 stimulation conditions observed in the intestinal environment.

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Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasis

Abstract: Axl expression is induced by TGF-β1 during Langerhans cell differentiation and enhances apoptotic cell uptake and blocks proinflammatory cytokine production.

Cited by 102 publications

References 51 publications

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses

TAM Receptor–Dependent Regulation of SOCS3 and MAPKs Contributes to Proinflammatory Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages

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