Heinz LX, Platzer B, Reisner PM et al.Differential involvement of PU.1 and Id2 downstream of TGF-beta1 during Langerhans-cell commitment. Blood 107:1445-1453

Institute of Immunology, Medical University Vienna, Lazarettgasse 19
Blood (Impact Factor: 10.45). 03/2006; 107(4):1445-53. DOI: 10.1182/blood-2005-04-1721
Source: PubMed


Langerhans cells (LCs) are highly abundant dendritic cells (DCs) in epidermal and mucosal tissues. The transcription factors PU.1 and Id2 have been implicated as positive regulators of LC development from hematopoietic progenitor cells. LC differentiation from progenitors is absolutely dependent on transforming growth factor beta 1 (TGF-beta1) in vitro as well as in vivo; however, downstream mechanisms are poorly defined. We found that both PU.1 and Id2 are induced by TGF-beta1 in human CD34+ monocyte/LC (M/LC) progenitor cells, and that neither ectopic PU.1 or Id2 alone, nor both together, could replace TGF-beta1 in its instructive function on LC commitment. However, both factors critically contributed to LC differentiation by acting at 2 distinct intersection points. Ectopic PU.1 strongly enhanced TGF-beta1-dependent LC development. Additionally, Notch-induced generation of interstitial-type DCs was associated with PU.1 up-regulation. Thus, PU.1 is generally increased during myeloid DC development. Ectopic Id2 inhibits the acquisition of early monocytic characteristics by cells generated in the absence of TGF-beta1 and also inhibits monocyte induction by alternative stimuli. Since TGF-beta1 represses a default monocyte pathway of common progenitor cells, PU.1 and Id2 seem to modulate lineage options of M/LC precursors, downstream of TGF-beta1.

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Available from: Herbert Strobl, Oct 13, 2014
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    • "The importance of TGF-β signaling in LCs lineage decisions has been demonstrated in RunX3 knockout (KO) and Id2KO mice. Deletion of these two signaling molecules downstream of the TGFβR abolished LC development [35, 58]. Reciprocal roles for C/EBP and PU.1 in LC development have also been identified [36, 59]. "
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    ABSTRACT: Immunosenescence is a result of progressive decline in immune system function with advancing age. Epidermal Langerhans cells (LCs), belonging to the dendritic cell (DC) family, act as sentinels to play key roles in the skin immune responses. However, it has not been fully elucidated how aging affects development and function of LCs. Here, we systemically analyzed LC development and function during the aging process in C57BL/6J mice, and performed global microRNA (miRNA) gene expression profiles in aged and young LCs. We found that the frequency and maturation of epidermal LCs were significantly reduced in aged mice starting at 12 months of age, while the Langerin expression and ability to phagocytose Dextran in aged LCs were increased compared to LCs from < 6 month old mice. The migration of LCs to draining lymph nodes was comparable between aged and young mice. Functionally, aged LCs were impaired in their capacity to induce OVA-specific CD4+ and CD8+ T cell proliferation. Furthermore, the expression of miRNAs in aged epidermal LCs showed a distinct profile compared to young LCs. Most interestingly, aging-regulated miRNAs potentially target TGF-β-dependent and non- TGF-β-dependent signal pathways related to LCs. Overall, our data suggests that aging affects LCs development and function, and that age-regulated miRNAs may contribute to the LC developmental and functional changes in aging.
    Full-text · Article · Nov 2012 · Aging
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    • "Differentiation of LCs is absolutely dependent on TGF-␤1 both in vitro and in vivo (Merad et al., 2008; Romani et al., 2010; Borkowski et al., 1996). TGF-␤1 induces PU.1 expression in CD34 + hematopoietic progenitor cells undergoing LC commitment, and ectopic expression of PU.1 strongly enhanced TGF-␤1-dependent LC development (Heinz et al., 2006). Interestingly, the miR-223 gene is driven by PU.1, and PU.1 repression down-regulates miR-223 expression (Fukao et al., 2007). "
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    ABSTRACT: Langerhans cells (LCs) are skin-residential dendritic cells that regulate skin immunity. MicroRNAs (miRNAs) are key regulators in the control of biological functions in a variety of cell types. Deletion of all miRNAs interrupts the homeostasis and function of epidermal LCs. However, the roles of individual miRNAs in regulating LC development and function are still completely unknown. MiRNA miR-233 is especially expressed in the myeloid compartment. Here, we reported that miR-223 is highly expressed in freshly isolated epidermal LCs, and tested whether miR-223 regulates LC development and function using miR-223 knockout (KO) mice. We found that the number, maturation, migration and phagocytic capacity of LCs were comparable between miR-223KO and wild-type mice. However, lack of miR-223 significantly increases LCs-mediated antigen-specific CD8(+) T cell proliferation in vivo and in vitro, while LCs from KO and WT mice showed comparable stimulation for antigen-specific CD4(+) T cells. Our data suggest that miR-223 negatively regulates LC cross-presentation, but may not be required for normal LC homeostasis and development.
    Full-text · Article · Nov 2012 · The international journal of biochemistry & cell biology
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    • "Manipulation of immune cell formation has become an important tool in studies of the molecular events of inflammation and wound healing. The PU.1 gene in mammals codes for a transcription factor that promotes myelopoiesis and differentiation of monocytes into macrophages , DCs, and LCs (Heinz et al., 2006). PU.1 null mice lack monocyte-derived cells but as neonates heal excisional skin wounds on the same schedule as wildtype wounds (Martin et al., 2003). "
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    ABSTRACT: The roles of inflammation and immune cell reactivity triggered by amputation have only recently begun to be addressed in investigations of epimorphic regeneration, although studies of tissue repair in mammals clearly show the importance of the immune system in determining the quality of the repair process. Here, we first review inflammation-related work in non-mammalian systems of epimorphic regeneration which suggests that regeneration of an amputated appendage requires continuous modulation of the local immune response, from the first hours after amputation through the period of blastema patterning. We then present data on the effects of anti-inflammatory and proinflammatory agents on regeneration of larval Xenopus hindlimbs. Treatment with the glucocorticoid beclomethasone immediately after amputation inhibits regeneration in regeneration-complete stage 53 limbs. Other anti-inflammatory agents, including the inhibitors of cyclooxygenase-2 (COX-2) activity celecoxib and diclofenac, applied similarly to larvae amputated at stage 55, when the capacity for limb regeneration is normally being lost, restore regenerative capacity. This suggests that although injury-related events sensitive to glucocorticoids are necessary for regeneration, resolution of the inflammatory response may also be required to allow the complete regenerative response and normal blastema patterning. Conversely, if resolution of inflammation is prevented by local treatment of amputated limbs with beryllium, a strong immunoadjuvant, regeneration is inhibited, and gene expression data suggest that this inhibition results from a failure of normal blastema patterning. Both positive and negative effects of immune- or inflammation-related activities occur during anuran limb regeneration and this underscores the importance of considering immune cells in studies of epimorphic regeneration. Anat Rec, 2012. ©2012 Wiley Periodicals, Inc.
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