Masatoshi Watanabe

In recent years, attention has increasingly focused on various infectious diseases. Although some fatalities are directly attributed to the causative virus, many result from complications and reactive inflammation. Patients with comorbidities are at a higher risk of mortality. Refractory skin conditions such as atopic dermatitis, psoriasis, and epidermolysis bullosa, known for an elevated risk of sepsis, partly owe this to compromised surface barrier function. However, the detailed mechanisms underlying this phenomenon remain elusive. Conversely, although the detrimental effects of a high-fat diet on health, including the onset of metabolic syndrome, are widely recognized, the association between diet and susceptibility to sepsis has not been extensively explored. In this study, we examined the potential causes and pathogenesis of increased sepsis susceptibility in inflammatory skin diseases using a mouse dermatitis model: keratin 14-driven caspase-1 is overexpressed (KCASP1Tg) in mice on a high-fat diet. Our findings reveal that heightened mortality in the dermatitis mouse model is caused by the inflamed immune system due to the chronic inflammatory state of the local skin, and administration of LPS causes a rapid increase in inflammatory cytokine levels in the spleen. Intake of a high-fat diet exacerbates these cytokine levels. Interestingly, we also observed a reduced expression of Toll-like receptor 4 (TLR4) in monocytes from KCASP1Tg mice, potentially predisposing these animals to heightened infection risks and associated complications. Histological analysis showed a clear decrease in T and B cells in the spleen of KCASP1Tg mice fed a high-fat diet. Thickening of the alveolar wall, inflammatory cell infiltration, and alveolar hemorrhage were more prominent in the lungs of KCASP1Tg and KCASP1Tg with fat mice. We postulate that the chronic, non-infectious inflammation induces a negative feedback loop within the inflammatory cascade, and the suppressed expression of TLR4 renders the mice more susceptible to infections. Therefore, it is imperative for individuals with chronic skin inflammation to closely monitor disease progression upon infection and seek timely and appropriate treatment. Additionally, chronic inflammation of adipose tissue, induced by high-fat food intake, combined with dermatitis inflammation, may exacerbate infections, necessitating a review of dietary habits.

Androgen deprivation therapy (ADT) targeting androgen production and androgen receptor (AR) signaling is the primary antihormonal therapy in the treatment of advanced prostate cancer (PCa). However, no clinically established molecular biomarkers have been identified to predict the effectiveness of ADT before starting ADT. The tumor microenvironment of PCa contains fibroblasts that regulate PCa progression by producing multiple soluble factors. We have previously reported that AR‐activating factor‐secreted fibroblasts increase the responsiveness of androgen‐sensitive, AR‐dependent PCa cells to ADT. Thus, we hypothesized that fibroblast‐derived soluble factors may affect cancer cell differentiation by regulating cancer‐related gene expression in PCa cells and that the biochemical characteristics of fibroblasts may be used to predict the effectiveness of ADT. Here, we investigated the effects of normal fibroblasts (PrSC cells) and three PCa patient‐derived fibroblast lines (pcPrF‐M5, ‐M28, and ‐M31 cells) on the expression of cancer‐related genes in androgen‐sensitive, AR‐dependent human PCa cells (LNCaP cells) and three sublines showing different androgen sensitivities and AR dependencies. The mRNA expression of the tumor suppressor gene NKX3‐1 in LNCaP cells and E9 cells (which show low androgen sensitivity and AR dependency) was significantly increased by treatment with conditioned media from PrSC and pcPrF‐M5 cells but not from pcPrF‐M28 and pcPrF‐M31 cells. Notably, no upregulation of NKX3‐1 was observed in F10 cells (AR‐V7‐expressing, AR‐independent cells with low androgen sensitivity) and AIDL cells (androgen‐insensitive, AR‐independent cells). Among 81 common fibroblast‐derived exosomal microRNAs that showed 0.5‐fold lower expression in pcPrF‐M28 and pcPrF‐M31 cells than in PrSC and pcPrF‐M5 cells, miR‐449c‐3p and miR‐3121‐3p were found to target NKX3‐1 . In only LNCaP cells, the NKX3‐1 mRNA expression was significantly increased by transfection of an miR‐3121‐3p mimic but not that of the miR‐449c‐3p mimic. Thus, fibroblast‐derived exosomal miR‐3121‐3p may be involved in preventing the oncogenic dedifferentiation of PCa cells by targeting NKX3‐1 in androgen‐sensitive, AR‐dependent PCa cells.