Biology subjects

Radtke, D.

Publications and source records attributed to Radtke, D..

5 recordsLinked to original sources

bioRxiv2026

Persistent activation of STAT6 in keratinocytes elicits neutrophilic skin inflammation, pruritus and S. aureus colonization reminiscent of chronic atopic dermatitis

Atopic dermatitis (AD) evolves from initial type 2 immunity-driven inflammation to chronic mixed responses by poorly understood mechanisms. To investigate how the prolonged activation of the usually IL-4/IL-13-induced transcription factor STAT6 in keratinocytes impacts on the development and subtype of AD, we generated a new mouse model in which a constitutively active form of STAT6 is selectively expressed in keratinocytes. These K14Cre+STAT6vt/vt mice spontaneously developed AD-like skin lesions characterized by Staphylococcus aureus colonization, neutrophilic inflammation, and pruritus starting at the age of 12-14 weeks. Treatment with antibiotics mitigated pathology, indicating that it is microbiota-driven. Comparison of human AD gene expression data with the transcriptome of skin biopsies from K14Cre+STAT6vt/vt mice revealed features shared with chronic AD, including genes associated with neutrophil and keratinocyte activation. Furthermore, heterozygous K14Cre+STAT6vt/wt mice developed a mixed eosinophilic and neutrophilic skin inflammation with exacerbated pathology compared to wild-type controls in an induced model of atopic dermatitis, compatible with chronic AD. These results indicate that persistent STAT6 activity in keratinocytes facilitates S. aureus outgrowth on the skin, promotes a type 1-/type 3-biased immune response, and is sufficient to mimic the transition from acute type 2 immunity-to chronic type 1-/type 3-immunity-dominated AD.

immunology↗

bioRxiv2025

ILC2s govern imprinting of alveolar macrophage-mediated immunity upon secondary helminth infection in the lung

Hookworm parasites migrate through the pulmonary system as part of their lifecycle, causing significant tissue damage that activates tissue-resident cell populations such as ILC2s. These cells drive type 2 immune responses critical for wound healing and the development of protective immunity. Macrophages, particularly monocyte-derived macrophages that seed the lung after infection, are central effectors of these responses and may be distinct from the tissue-resident populations they replace. However, the cellular and molecular factors governing the attrition of tissue-resident (TR) macrophages and their replacement remain poorly understood. We find that ILC2s and IL-4/IL-13-producing CD4+ T cells bi-directionally interact to regulate alveolar macrophage (AM) populations during infection. In the absence of these cells, type 2 immune responses are muted, leading to impaired anti-parasitic immunity in the lung during re-infection. This correlates with diminished expansion of type 2-polarized monocyte-derived alveolar macrophages (Mo-AMs), which are metabolically and transcriptionally distinct from TR-AMs. While Mo-AMs highly upregulated expression of Arg1, this was not essential for development of protective immunity in the lung. Concomitant with a more glycolytic metabolism, ILC2-induced Mo-AMs selectively upregulate arachidonate 15-lipoxygenase (Alox15), which promotes the capacity of macrophages to attack parasites in vitro. These results identify ILC2s as critical regulators of alveolar macrophage dynamics and important mediators of their function during helminth infection of the lung.

immunology↗

bioRxiv2025

Il33 expressing cDC2s promote expansion of ILC2s and eosinophilia in fungal airway inflammation in male mice

Eosinophilic allergic asthma is often associated with fungal sensitization and represents the dominant form of asthma in adolescents. The mechanisms by which lung eosinophilia is regulated in this context are incompletely understood. Here, we demonstrate that type 2 innate lymphoid cells (ILC2s) are generally required in addition to Th2 cells for Aspergillus fumigatus-elicited eosinophilic lung inflammation in mice and this effect was independent of ILC2-derived IL-5. Surprisingly, expansion of ILC2s in male mice was ST2-independent, but required expression of Il33 in cDC2s induced by Th2-derived IL-4/13. This IL-33-plus IL-4-regulated transcriptional module in cDC2s included expression of factors associated with activation of ILC2s and was restricted to CCR7+ cDC2s in the inflamed lung. Our findings uncovered a novel intimate cross-talk between IL-33+ cDC2s, ILC2s and Th2 cells to orchestrate eosinophilia in a sex-dependent manner upon A. fumigatus-induced allergic lung inflammation.

immunology↗

bioRxiv2025

The metabolic program of inflammatory eosinophils accounts for chronic parasite-induced skin-disease

Eosinophils exert antimicrobial, cytotoxic and immunoregulatory effects, but their function in cutaneous tissue still remains poorly understood. Here, we used a mouse model of chronic cutaneous leishmaniasis caused by the protozoan parasite Leishmania (L.) mexicana to investigate the function and transcriptomic signature of eosinophils in the skin. In C57BL/6 wild-type mice, L. mexicana infection induced local and systemic eosinophilia that was dependent on type 2 innate lymphoid cells and interleukin-5. Genetic and pharmacological depletion of eosinophils led to complete clinical resolution of disease, which was accompanied by a more pronounced Th1 and M1-like macrophage response. Bioinformatic analyses revealed a novel inflammatory and tissue-specific transcriptional trajectory in skin-infiltrating eosinophils. Skin-imprinted eosinophils strongly expressed the high-affinity glucose transporter 3 (Slc2a3), deprived the environment of glucose and directly impeded the function of Th1 cells. Together, our results demonstrate that disease progression and chronicity of L. mexicana infection is caused by inflammatory eosinophils and linked to their metabolic program. Short SummaryThe authors describe that depletion of eosinophils prevents chronic cutaneous disease caused by Leishmania mexicana. They identify a novel, tissue-specific transcriptomic profile of inflammatory skin eosinophils and demonstrate that skin-imprinted eosinophils show strong glucose uptake and directly repress Th1 responses. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/640104v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@3ecd3org.highwire.dtl.DTLVardef@1b1283forg.highwire.dtl.DTLVardef@1c941fdorg.highwire.dtl.DTLVardef@b7c39_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSO_LIEosinophil accumulation precedes the development of chronic cutaneous leishmaniasis C_LIO_LIEosinophil depletion or IL-5 neutralization lead to clinical cure of the disease C_LIO_LIL. mexicana infection elicits a unique transcriptomic signature of skin eosinophils C_LIO_LISkin eosinophils show a marked uptake of glucose and directly repress Th1 responses C_LI

immunology↗

bioRxiv2021

Th2 single-cell heterogeneity and clonal interorgan distribution in helminth-infected mice

Th2 cells provide effector functions in type 2 immune responses to helminths and allergens. Despite knowledge about molecular mechanisms of Th2 cell differentiation, there is little information on Th2 cell heterogeneity and clonal distribution between organs. To address this, we performed combined single-cell transcriptome and TCR clonotype analysis on murine Th2 cells in mesenteric lymph nodes (MLN) and lung after infection with Nippostrongylus brasiliensis (Nb) as a human hookworm infection model. We find organ-specific expression profiles, but also populations with conserved migration or effector/resident memory signatures that unexpectedly cluster with potentially regulatory Il10posFoxp3neg cells. A substantial MLN subpopulation with an interferon response signature suggests a role for interferon-signaling in Th2 differentiation or diversification. Further RNA-inferred developmental directions indicate proliferation as a hub for differentiation decisions. We also link long noted Cxcr3 expression in the Th2 compartment to a population of Il4pos NKT cells. Although the TCR repertoire is highly heterogeneous, we identified expanded clones and CDR3 motifs. Clonal relatedness between distant organs confirmed effective exchange of Th2 effector cells, although locally expanded clones dominated the response. These results provide new insights in Th2 cell subset diversity and clonal relatedness in distant organs.

immunology↗