Competition for Active TGFß Cytokine Allows for Selective Retention of Antigen-Specific Tissue- Resident Memory T Cells in the Epidermal Niche.

Following antigen-driven expansion in lymph node, transforming growth factor-ß (TGFß) is required for differentiation of skin-recruited CD8+ T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFß -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFß was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFßR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFß represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche.

Keratinocyte-Mediated Activation of the Cytokine TGF-ß Maintains Skin Recirculating Memory CD8+ T Cells.

Regulated activation of the cytokine TGF-ß by integrins αvß6 and αvß8 expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV) infection, antigen-specific circulating memory CD8+ T cells migrated into skin. In mice lacking αvß6 and αvß8 integrins (Itgb6-/-Itgb8fl/fl-K14-cre), the absence of epidermal-activated TGF-ß resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool.

Nail findings in patients with psoriatic arthritis: A cross-sectional study with special reference to transverse grooves.

BACKGROUND: Patients with psoriatic arthritis (PsA) commonly present with nail manifestations; however, little is known about these manifestations. OBJECTIVE: This study investigated whether nail findings can be used to discriminate between PsA and psoriasis without arthritis. METHODS: We performed a retrospective analysis of 118 patients with PsA and 974 patients with psoriasis without arthritis who visited St. Luke's International Hospital (Tokyo, Japan) between July 2003 and February 2015. Patients with PsA were classified according to the Classification of Psoriatic Arthritis criteria. Skin lesion severity was assessed by using the Psoriasis Area and Severity Index, and 9 types of nail findings were investigated. RESULTS: The incidence of nail involvement in patients with PsA was 67.6%. Female sex, presence of transverse grooves, onycholysis, and splinter hemorrhages were significantly related to PsA, with transverse grooves demonstrating the strongest association (odds ratio, 5.01; 95% confidence interval, 2.31-10.8; P < .01). Furthermore, the presence of transverse grooves was strongly related to both distal interphalangeal arthritis and enthesitis. LIMITATIONS: The PsA population was relatively small. CONCLUSIONS: Nail findings enabled us to distinguish patients with PsA from those without arthritis. The presence of transverse grooves is significantly associated with PsA and may be associated with distal interphalangeal arthritis and enthesitis.

TNF-α and IL-1ß Do Not Induce Langerhans Cell Migration by Inhibiting TGFß Activation.

In the skin, Langerhans cells (LCs) require autocrine latent TGFß that is transactivated by the integrins ανß6 and ανß8 expressed by keratinocytes (KCs) for long-term epidermal retention. Selective expression of a ligand-independent, constitutively active form of TGFßR1 inhibits LC migration during homeostasis and in response to UVB exposure. In this study, we found that LC migration in response to inflammatory stimuli was also inhibited by ligand-independent TGFßR1 signaling. Contrary to UVB stimulation, which reduced KC expression of ανß6, in vitro and in vivo exposure to TNF-α or IL-1ß increased ανß6 transcript and protein expression by KCs. This resulted in increased KC-mediated transactivation of latent TGFß. Expression of ανß8 was largely unchanged. These findings show that ligand-independent TGFßR1 signaling in LCs can overcome inflammatory migration stimuli, but reduced KC-mediated transactivation of latent TGFß by KCs may only drive LC migration during homeostasis and in response to UV stimulation.

MR Imaging of Mushroom-like Skin Adnexal Tumors in the Scalp: A Report of Two Cases.

Few studies had been published regarding imaging findings of skin adnexal tumors. We experienced two giant cases of them with a characteristic mushroom-like growth pattern. MRI showed a circumscribed mushroom-like shaped mass extruding from the subcutaneous tissue with microcystic lesions. Although differentiation between benignancy and malignancy may be difficult by radiological examinations, MRI may be helpful to identify its origin and differentiate soft tissue tumors with skin adnexal tumors in having these imaging findings.

Keratinocyte-derived TGFß is not required to maintain skin immune homeostasis.

BACKGROUND: Transforming growth factor beta 1 (TGFß) is known to be a regulator of autoimmunity. Loss of TGFß leads to severe multi-organ autoimmunity in mice. In skin, role of TGFß in suppressing autoimmunity is unclear. OBJECTIVE: Determine whether Keratinocyte (KC)-derived TGFß is required for skin immune homeostasis. METHODS: We generated K14-CreERT2TGFß1fl/fl (TGFßΔKC) mice allowing for tamoxifen-induced deletion of TGFß1 in KC. The phenotype of skin was analyzed and compared to mice in which epidermal activation of TGFß is impaired. RESULTS: KC was the major source of TGFß in epidermis. Topical tamoxifen application led to efficient TGFß1 deletion. The expected acanthosis was observed but no inflammatory infiltrate or altered numbers of resident immune cells were evident. Similarly, Itgb6-/-x K14Cre Itgb8f/f (Itgb6-/-Itgb8ΔKC) mice lacking both epidermal TGFß-activating integrins showed no evidence of cutaneous inflammation. CONCLUSIONS: KC-derived TGFß and epidermal TGFß activation are not required to suppress skin autoimmunity in steady state.

Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2.

Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes and antioxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of such stimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap1 and rapid degradation through the proteasome system. We examined the contribution of Keap1 to the rapid turnover of Nrf2 (half-life of less than 20 min) and found that a direct association between Keap1 and Nrf2 is required for Nrf2 degradation. In a series of domain function analyses of Keap1, we found that both the BTB and intervening-region (IVR) domains are crucial for Nrf2 degradation, implying that these two domains act to recruit ubiquitin-proteasome factors. Indeed, Cullin 3 (Cul3), a subunit of the E3 ligase complex, was found to interact specifically with Keap1 in vivo. Keap1 associates with the N-terminal region of Cul3 through the IVR domain and promotes the ubiquitination of Nrf2 in cooperation with the Cul3-Roc1 complex. These results thus provide solid evidence that Keap1 functions as an adaptor of Cul3-based E3 ligase. To our knowledge, Nrf2 and Keap1 are the first reported mammalian substrate and adaptor, respectively, of the Cul3-based E3 ligase system.

Large pulmonary arteriovenous malformation with hyperammonemia.

A 45-year-old female presented with generalized fatigue, unaccompanied by other symptoms. Investigation revealed severe anemia due to gastric bleeding, and hereditary hemorrhagic telangiectasia accompanied by a large pulmonary arteriovenous malformation (PAVM). Additionally, the presence of hepatic arteriovenous and portovenous shunts indicated hepatic involvement. In addition to hypoxemia due to right-to-left shunting in PAVM, hyperammonemia with normal hepatic function was detected. The large PAVM was successfully managed with surgical resection. Hyperammonemia, persisting despite the hemostasis of gastric bleeding, improved postoperatively in the absence of treatment directed at hepatic involvement. We believe that resection of large PAVM contributed to the improvement of hyperammonemia.

Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network.

Small Maf proteins serve as dual-function transcription factors through an exchange of their heterodimerization partners. For example, as heterodimers with hematopoietic cell-specific p45 NF-E2 or NF-E2-related factors (Nrf), they activate the beta-globin or antioxidative stress enzyme heme oxygenase 1 (HO-1) genes, respectively. In contrast, together with Bach1, they repress these same genes. However, the signals leading to this partner exchange are not known. Using chromatin immunoprecipitation assays in NIH 3T3 cells, we show that heme, an inducer of ho-1, promotes displacement of Bach1 from the MafK-occupied ho-1 enhancers, which is followed by Nrf2 binding to these elements. Whereas histone H3 at the ho-1 enhancers and promoter is hyperacetylated irrespective of gene activity, exposure of cells to heme results in de novo hyperacetylation and hypermethylation of histone H3 in the transcribed region. These data indicate that, under normal conditions, the chromatin structure of ho-1 is in a preactivation state, but transcription is repressed by Bach1. Heme induces switching of Maf dimers, resulting in ho-1 expression. Heme also promotes displacement of Bach1 from the beta-globin locus control region without affecting MafK binding in murine erythroleukemia cells. Thus, heme functions as a signaling molecule for gene expression in higher eukaryotes.

Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1.

Bach1 is a transcriptional repressor of heme oxygenase-1 and beta-globin genes, both of which are known to be transcriptionally induced by heme. To test the hypothesis that heme regulates the activity of Bach1, we expressed wild type and mutated versions of Bach1 together with or without its heterodimer partner MafK in human 293T and GM02063 cells and examined their subcellular localization. Inhibition of heme synthesis enhanced the nuclear accumulation of Bach1, whereas treating cells with hemin resulted in nuclear exclusion of Bach1. While the cadmium-inducible nuclear export signal (NES) of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs was found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated NES dependent on the exporter Crm1. These results extend the regulatory roles for heme in protein sorting, and suggest that Bach1 transduces metabolic activity into gene expression.