Biology subjects

Mou, W.

Publications and source records attributed to Mou, W..

3 recordsLinked to original sources

bioRxiv2026

Dual blockade of IL-18 and IL-4Rα by a bispecific antibody for improved treatment of atopic dermatitis

Background: Atopic dermatitis (AD) is a chronic inflammatory dermatosis primarily driven by type 2 immunity, with additional type 1 and type 3 components that may limit the benifit of ILRalpha blockade alone. Interleukin18 (IL18), an epithelial alarmin genetically associated with AD and correlated with disease severity, has been implicated as an upstream amplifier of this mixed inflammatory response. Objective: To assess whether concurrent IL18 neutralization and IL4Ralpha; blockade with a bispecific antibody provides broader and more balanced suppression of AD relevant type 1, type 2, and type 3 pathways than single target inhibition. Methods: We generated FJ0125, a bispecific antibody comprising human IL18 binding protein fused to a novel humanized anti IL4Ralpha antibody, and characterized its binding, signaling, and functional activity in vitro and in vivo. The activity was evaluated in human group 2 innate lymphoid cell and primed Th2 cell assays, a keratinocyte & dendritic cell & T cell coculture system, and an MC903/Staphylococcus aureus induced dermatitis model in human IL4/IL4Ralpha; knock in mice. Results: FJ0125 bound to IL18 and IL4Ralpha; with high affinity, engaged both targets, inhibited IL4/IL13 signaling with dupilumab comparable potency, and neutralized human and mouse IL18. In vitro, FJ0125 more effectively suppressed IL18 driven lymphocyte activation and type 1, type 2, and type 3 cytokine production than IL18BPFc or IL4Ralpha; monotherapy. In vivo, FJ0125 reduced multitype cytokines, improved dermatitis, lowered serum IgE, and abrogated the paradoxical IL22 increase observed with selective IL4Ralpha; blockade. Conclusion: Dual IL18/IL4Ralpha; blockade with FJ0125 achieves coordinated suppression of multitype inflammation and represents a mechanistically substantiated therapeutic strategy for AD.

immunology↗

bioRxiv2024

1-Aminocyclopropane-1-carboxylic acid oxidase determines the fate of ethylene biosynthesis in a tissue-specific way to fine-tune development and stress resilience

Ethylene is involved in several developmental processes and responses towards (a)biotic stress. In seed plants, ethylene is produced from its precursor 1-aminocyclopropane-1-carboxylic acid (ACC) by the enzyme ACC-oxidase (ACO). Despite its key role in ethylene synthesis, the ACO gene family has not yet been fully characterized. We investigated the five ACO members of Arabidopsis thaliana and revealed a tissue-and developmentally specific expression pattern. Furthermore, the five ACO enzymes each have a different capacity to produce ethylene. Combined, this allows for a precise spatial and temporal regulation of ethylene synthesis. At the sub-cellular level, we uncovered that ACOs reside in the cytosol, where ethylene is likely synthesized, but surprisingly also in the nucleus. Using reverse genetics of single and higher order aco mutants we revealed a high degree of gene redundancy and minimal phenotypes. A lack of ethylene synthesis by knocking out all five ACOs did not impair normal vegetative and generative development but did influence processes associated with high rates of ethylene production such as petal abscission. This suggests that ethylene is not a prime regulator of development, but more a moderator. We also showed that the inability to synthesize ethylene impairs some abiotic (nutrient deficiency and metal toxicity) and biotic (Botrytis cinerea) stress responses, similar as plants insensitive towards ethylene, corroborating the role of ethylene in mediating stress responses. In conclusion, the ACO gene family enables plants to fine-tune their ethylene synthesis rates, but a lack their off is not crucial for normal development and stress survival.

plant biology↗

bioRxiv2022

Ethylene Insensitive 3-Like 2 (EIL2) is a Brassicaceae-specific transcriptional regulator involved in fine-tuning ethylene-dependent hypocotyl elongation, lateral root formation and flowering time in Arabidopsis thaliana

Ethylene signaling directs a pleiotropy of developmental processes in plants. In Arabidopsis, ethylene signaling converges at the master transcription factor Ethylene Insensitive 3 (EIN3), which has five homologs, EIN3-like 1-5 (EIL1-5). EIL1 is most characterized and operates similar as EIN3, while EIL3-5 are not involved in ethylene signaling. EIL2 remains less investigated. Our phylogenetic analysis revealed that EIL2 homologs are only retrieved in the Brassicaceae family, suggesting EIL2 diverged to have specific functions in the mustard family. By characterizing eil2 mutants, we found that EIL2 is involved in regulating ethylene-specific developmental processes in Arabidopsis thaliana, albeit in a more subtle way compared to EIN3/EIL1. EIL2 steers ethylene-triggered hypocotyl elongation in light-grown seedlings and it is involved in lateral root formation. Furthermore, EIL2 takes part in regulating flowering time as eil2 mutants flower on average one day earlier and have fewer leaves. A pEIL2:EIL2:GFP translational reporter line revealed that EIL2 protein abundance is restricted to the stele of young developing roots. EIL2 expression, and not EIL2 protein stability, is regulated by ethylene in an EIN3/EIL1-dependent way. Despite EIL2 taking part in several developmental processes, the precise upstream and downstream regulation of this ethylene- and Brassicaceae-specific transcription factor remains to be elucidated. HighlightEIL2 is an ethylene-dependent transcription factor that evolved exclusively in the mustard family and operates downstream from EIN3/EIL1. EIL2 is involved in fine-tuning hypocotyl elongation, lateral root formation and flowering time in Arabidopsis thaliana.

molecular biology↗