The use of hydrogel-based niches for therapy delivery enables the concentration of active components and cells in a targeted area. This approach enhances efficacy while minimizing systemic side effects by spatially controlling the release of the therapy. Precise tuning of the matrix's chemical properties and control of both material degradation and release profile of biologically active components are required to reduce the optimal dose and extend its therapeutic effect. Here we aimed to develop an injectable hydrogel that can fulfill all these requirements. We designed a system based on hyaluronic acid, crosslinked via click-reaction with multi-arm polyethyleneglycol and functionalized with RGD peptides. Additionally, we incorporated thiol-modified heparin into the formulation, which provides specific binding sites for cytokines. Our results indicate that heparin incorporation can delay cytokine release, while the release of nanocarriers can be regulated by adjusting the crosslinking degree. This design modulates pore size and degradation time, while preserving the injectability of the niche. In conclusion, this system offers a versatile and efficient delivery platform suitable for therapeutic applications in a wide range of diseases.
© 2025 The Authors. Published by Elsevier Ltd.

Cryptococcosis is a neglected fungal disease that causes many deaths annually, is primarily caused by Cryptococcus neoformans and Cryptococcus gattii species. They are environmental fungus that engages lung pneumonia and a severe systemic infection. The rising incidence of affected immunocompetent hosts, particularly by the aggressive Cryptococcus deuterogattii (R265), underscores the urgency to understand factors influencing its dissemination. The immunopathogenesis of R265 infection is incompletely understood. Therefore, we investigate the role of IL-22 and IL-23 cytokines during R265 cryptocococcosis. Our findings highlight the crucial role of IL-22 and IL-23 cytokines in lung barrier homeostasis, preventing excessive lung damage. IL-22 not only prevents neutrophil infiltration and IL-17A production but also facilitates eosinophil lung infiltration. Ultimately, this study contributes vital insights into the selective role of IL-22 and IL-23 cytokines in immune activation and tissue regulation during the aggressive R265 lung and systemic infection.
© 2024 The Author(s).

Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKβ and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.
© 2024. The Author(s).

Cancer cells accumulate epigenetic modifications that allow escape from intrinsic and extrinsic surveillance mechanisms. In the case of acute myeloid leukemias (AML) and myelodysplastic syndromes, agents that disrupt chromatin structure, namely hypomethylating agents (HMAs), have shown tremendous promise as an alternate, milder treatment option for older, clinically non-fit patients. HMAs reprogram the epigenetic landscape in tumor cells through the reversal of DNA hypermethylation. Therapeutic effects resulting from these epigenetic changes are incredibly effective, sometimes resulting in complete remissions, but are frequently lost due to primary or acquired resistance. In this study, we describe syngeneic murine leukemias that are responsive to the HMA 5-azacytidine (5-Aza), as determined by augmented expression of a transduced luciferase reporter. We also found that 5-Aza treatment re-established immune-related transcript expression, suppressed leukemic burden and extended survival in leukemia-challenged mice. The effects of 5-Aza treatment were short-lived, and analysis of the immune microenvironment reveals possible mechanisms of resistance, such as simultaneous increase in immune checkpoint protein expression. This represents a model system that is highly responsive to HMAs and recapitulates major therapeutic outcomes observed in human leukemia (relapse) and may serve as a pre-clinical tool for studying acquired resistance and novel treatment combinations.

To facilitate the recovery process of chronic and hard-to-heal wounds novel pro-resolving treatment options are urgently needed. We investigated the pro-regenerative properties of soluble CD83 (sCD83) on cutaneous wound healing, where sCD83 accelerated wound healing not only after systemic but also after topical application, which is of high therapeutic interest. Cytokine profile analyses revealed an initial upregulation of inflammatory mediators such as TNFα and IL-1β, followed by a switch towards pro-resolving factors, including YM-1 and IL-10, both expressed by tissue repair macrophages. These cells are known to mediate resolution of inflammation and stimulate wound healing processes by secretion of growth factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which promote vascularization as well as fibroblast and keratinocyte differentiation. In conclusion, we have found strong wound healing capacities of sCD83 beyond the previously described role in transplantation and autoimmunity. This makes sCD83 a promising candidate for the treatment of chronic- and hard-to-heal wounds.
Copyright © 2022 Royzman, Peckert-Maier, Stich, König, Wild, Tauchi, Ostalecki, Kiesewetter, Seyferth, Lee, Eming, Fuchs, Kunz, Stürmer, Peters, Berking, Zinser and Steinkasserer.