Diet can impact on gut health and disease by modulating intestinal stem cells (ISCs). However, it is largely unknown if and how the ISC niche responds to diet and influences ISC function. Here, we demonstrate that Lepr⁺ mesenchymal cells (MCs) surrounding intestinal crypts sense diet change and provide a novel niche signal to maintain ISC and progenitor cell proliferation. The abundance of these MCs increases upon administration of a high-fat diet (HFD) but dramatically decreases upon fasting. Depletion of Lepr⁺ MCs resulted in fewer intestinal stem/progenitor cells, compromised the architecture of crypt–villus axis and impaired intestinal regeneration. Furthermore, we showed that IGF1 secreted by Lepr⁺ MCs is an important effector that promotes proliferation of ISCs and progenitor cells in the intestinal crypt. We conclude that Lepr⁺ MCs sense diet alterations and, in turn, modulate intestinal stem/progenitor cell function via a stromal IGF1–epithelial IGF1R axis. These findings reveal that Lepr⁺ MCs are important mediators linking systemic diet changes to local ISC function and might serve as a novel therapeutic target for gut diseases.

Green tea extracts and tea catechins have been shown to prevent or alleviate diabetes. The present study tests the hypothesis that green tea leaves in powder form (GTP), which also contain fiber and other water non-extractable materials, are more effective than the corresponding green tea extracts (GTE) in impeding the development of diabetes in db/db mice. Female db/db mice were treated with a diet containing 1% of GTE, 2% of GTE, 2% of GTP (with the same catechin content as 1% GTE) or 1% GTP. The 1% GTE group had lower food intake, water consumption, body weight and fasting blood glucose levels than the control group, while 2% GTP did not have any significant effect. Dietary 1% GTE also preserved β-cell insulin secretion. However, 1% GTP increased food intake, water consumption and blood glucose levels. Microbiome analysis with 16S rRNA gene V4 sequencing showed that the gut microbiota was modified by GTE and GTP, and a few bacterial guilds were associated with blood glucose levels. In the Random Forest regression model, the leading predictor of metabolic outcome was food consumption, followed by changes in some bacterial guilds. The results illustrate the importance of food consumption and gut microbiota in affecting the progression of diabetes.

The stress-induced keratin 16 intermediate filament gene, KRT16 , and K16 protein are spatially restricted to the suprabasal layers of the epidermis and widely used as biomarkers in psoriasis, hidradenitis suppurativa, atopic dermatitis, and other inflammatory disorders. Pathogenic variants in KRT16 cause pachyonychia congenita (PC), a rare genetic condition in which tissue homeostasis is disrupted in palmoplantar epidermis, nail, oral mucosa, and other KRT16 -expressing epithelial appendages. How K16 may regulate the molecular mechanisms underlying these conditions is poorly understood. Here, we show that K16 negatively regulates type I interferon (IFN) signaling and innate immune responses in skin. Clinically, the signature palmoplantar keratoderma lesions in individuals with PC showed enhanced type I IFN signaling. In mouse skin in vivo, loss of Krt16 led to exacerbation of imiquimod-induced psoriasiform disease and heightened recruitment of neutrophils in a phorbol ester–induced model of acute sterile inflammation. In KRT16 -null human keratinocytes, loss of K16 amplified IFN signaling including phosphorylated interferon regulatory factor 7 (IRF7) and interferon-stimulated gene 15 (ISG15) after treatment with synthetic dsRNA poly(I:C). Mechanistically, K16 interacted with effectors of the RIG-I–like receptor (RLR) pathway, including 14-3-3ɛ, and inhibited the 14-3-3ɛ:RIG-I interaction upstream of IFN activation in mouse and immortalized human keratinocytes ex vivo. Topical application of the Janus kinase inhibitor cream ruxolitinib to palmoplantar keratoderma lesions of Krt16 -null mice reduced lesion severity. These findings uncover a previously unrecognized paradigm for keratin-dependent regulation of innate immunity, with implications for our understanding of inflammatory skin diseases and potential treatments for PC.

To the Editor We read with great interest the article published in JAMA Oncology by Berner and colleagues, which was the first study, to our knowledge, to show a potential mechanism of skin immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Clinical studies have enhanced the understanding of irAEs in a clinical but not pathophysiological view. This study found that patients with non–small cell lung cancer who were treated with a programmed cell death 1 (PD-1) inhibitor and experienced skin irAEs had a higher response rate and longer overall survival than those without skin irAEs. By analyzing the T-cell receptor (TCR) clones from peripheral blood mononuclear cells, tumor biopsy specimens, and biopsy specimens from the sites of skin irAEs, Berner et al revealed that some shared antigens were present in both lung tumors and the skin. The study had meaningful findings, and we support most of the conclusions, but we have several concerns about the study.First, the duration of treatment may be an important confounding factor that could affect the association between irAEs and efficacy. Longer duration of ICI treatment has been associated with a higher rate of adverse events. However, the treatment duration was not reported in this study. Duration of treatment and onset time of skin irAEs should be reported to better explain the conclusion.The second concern is about the site from which the pretreatment tumor specimen was obtained for the sequencing. With a better understanding of the temporal and spatial heterogeneity of the tumor, the primary tumor or metastasis site and advanced or recurrent disease provide different genomic information. In lung cancer, TCR intratumor heterogeneity has been reported. In addition, the dynamics of changes in the complementary determining region 3 of TCR during nivolumab treatment have been described. However, Berner et al did not address the site of the tumor sample. Knowing the site of the pretreatment tumor sample (primary tumor or metastasis) and the patients’ disease stage (advanced or recurrent) would help us to better understand the mechanism of skin irAEs associated with ICI therapy.The conclusion that lung tumors and the skin share some of the same self-antigens should be validated in larger cohort studies. If necessary, repeat tumor biopsy specimens obtained before and during treatment should be matched with specimens from the sites of skin irAEs to confirm a pathophysiological mechanism. Additional analysis of the pathophysiological mechanism will improve the understanding of irAEs, allowing clinicians to better manage them and to maximize the therapeutic efficacy of ICIs.

Neutrophils contribute to the pathogenesis of chronic inflammatory skin diseases. Little is known about the source and identity of the signals mediating their recruitment in inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin and assess whether keratinocyte-derived signals impact neutrophil recruitment. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12h and resolves within 24h. A second TPA treatment or a UVB challenge, when applied at 24h but not 48h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated in ex vivo culture, and involves the K17-dependent sustainment of protein kinase Cα (PKCα) activity and release of neutrophil chemoattractants by stressed keratinocytes. We show that K17 binds RACK1, a scaffold essential for PKCα activity. Finally, analyses of RNAseq data reveal the presence of a transcriptomic signature consistent with TAR and PKCα activation in chronic inflammatory skin diseases. These findings uncover a novel, transient, and keratin-dependent mechanism that amplifies neutrophil recruitment to the skin under stress, with direct implications for inflammatory skin disorders.