Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake.

Epithelial cells control a variety of immune cells by secreting cytokines to maintain tissue homeostasis on mucosal surfaces. Regulatory T (Treg) cells are essential for immune homeostasis and for preventing tissue inflammation; however, the precise molecular mechanisms by which epithelial cell-derived cytokines function on Treg cells in the epithelial tissues are not well understood. Here, we show that peripheral Treg cells preferentially respond to thymic stromal lymphoprotein (TSLP). Although TSLP does not affect thymic Treg differentiation, TSLP receptor-deficient induced Treg cells derived from naïve CD4+ T cells are less activated in an adoptive transfer model of colitis. Mechanistically, TSLP activates induced Treg cells partially through mTORC1 activation and fatty acid uptake. Thus, TSLP modulates the activation status of induced Treg through the enhanced uptake of fatty acids to maintain homeostasis in the large intestine.

Semaphorin 3G exacerbates joint inflammation through the accumulation and proliferation of macrophages in the synovium.

OBJECTIVES: Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA. METHODS: CD4+ T cells from 28 treatment-naïve patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated. RESULTS: Semaphorin 3G expression in CD4+ T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages. CONCLUSIONS: Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.

Determinants of fracture type in the proximal femur: Biomechanical study of fresh frozen cadavers and finite element models.

BACKGROUND: Proximal femur fractures are usually categorized as either a cervical or trochanteric fracture, but the relationship between fracture type and fall direction is not clear. By cadaveric mechanical testing and finite element analysis (FEA), the aims of this research were to verify the factors that define the proximal femur fracture type and to clarify the change in stress distribution based on fall direction. METHODS: From fresh frozen cadavers, we obtained 26 proximal femora including ten pairs of 20 femora. We conducted quasi-static compression tests in two fall patterns (lateral and posterolateral), and identified the fracture type. We then examined the relationship between fracture type and the following explanatory variables: age, sex, neck shaft angle, femoral neck length, bone mineral density (cervical and trochanteric), and fall direction. In addition, for the ten pairs of femurs, the effect of fall direction on fracture type was examined by comparing the left and right sides. In addition, we generated the proximal femur finite element (FE) models from computed tomography data to simulate and verify the change of external force in different fall directions. RESULTS: In mechanical tests, only fall direction was found to have a significant relationship with fracture type (p = 0.0227). The posterolateral fall group had a significantly higher incidence of trochanteric fractures than lateral fall group (p = 0.0325). According to FEA, the equivalent stress in the lateral fall was found to be more concentrated in the cervical area than in the posterolateral fall. CONCLUSION: In proximal femur fractures, fall direction was significantly associated with fracture type; in particular, trochanteric fractures were more likely to occur following a posterolateral fall than a lateral fall.