Biology subjects

Graf, L.-M.

Publications and source records attributed to Graf, L.-M..

3 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↗