32 research outputs found
Keratinocyte EGF signalling dominates in atopic dermatitis lesions: A comparative RNAseq analysis
Atopic dermatitis (AD) remains a highly heterogenous disorder with a multifactorial aetiology. Whilst keratinocytes are known to play a fundamental role in AD, their contribution to the overall immune landscape in moderateātoāsevere AD is still poorly understood. In order to design new therapeutics, further investigation is needed into common disease pathways at the molecular level. We used publicly available wholeātissue RNAseq data (4 studies) and singleācell RNAseq keratinocyte data to identify genes/pathways that are involved in keratinocyte responses in AD and after dupilumab treatment. Transcripts present in both keratinocytes (singleācell) and wholeātissue, referred to as the keratinocyteāenriched lesional skin (KELS) genes, were analysed using functional/pathway analysis. Following statistical testing, 2049 genes (16.8%) were differentially expressed in KELS. Enrichment analyses predicted increases in not only typeā1/typeā2 immune signalling and chemoattraction, but also in EGFādominated growth factor signalling. We identified complex crosstalk between keratinocytes and immune cells involving a dominant EGF family signature which converges on keratinocytes with potential immunomodulatory and chemotaxisāpromoting consequences. Although keratinocytes express the IL4R, we observed no change in EGF signalling in KELS after threeāmonth treatment with dupilumab, indicating that this pathway is not modulated by dupilumab immunotherapy. EGF family signalling is significantly dysregulated in AD lesions but is not associated with keratinocyte proliferation. EGF signalling pathways in AD require further study
Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis
The question of how the neural and immune systems interact in host defence is important, integrating a system that senses the whole body with one that protects. Understanding the mechanisms and routes of control could produce novel and powerful ways of promoting and enhancing normal functions as well as preventing or treating abnormal functions. Fragmentation of biological research into specialities has resulted in some failures in recognising and understanding interactions across different systems and this is most striking across immunology, haematology and neuroscience. This reductionist approach does not allow understanding of the in vivo orchestrated response generated through integration of all systems. However, many factors make the understanding of multisystem cross-talk in response to a threat difficult, for instance the nervous and immune systems share communication molecules and receptors for a wide range of physiological signals. But, it is clear that physical, hard-wired connections exist between the two systems, with the key link involving sensory, unmyelinated nerve fibres (c fibres) containing the neuropeptide calcitonin gene-related peptide (CGRP), and modified macrophages, mast cells and other immune and host defence cells in various locations throughout the body. In this review we will therefore focus on the induction of CGRP and its key role in the neuroimmune axis
Staphylococcus aureus Second Immunoglobulin-Binding Protein drives atopic dermatitis via IL-33
Trichuris muris infection drives cell-intrinsic IL4R alpha independent colonic RELMĪ±+ macrophages
From PLOS via Jisc Publications RouterHistory: received 2021-02-23, accepted 2021-06-29, collection 2021-07, epub 2021-07-30Publication status: PublishedFunder: Medical Research Council; funder-id: http://dx.doi.org/10.13039/501100000265; Grant(s): MR/N022661/1Funder: wellcome trust; funder-id: http://dx.doi.org/10.13039/100004440; Grant(s): 106898/A/15/ZThe intestinal nematode parasite Trichuris muris dwells in the caecum and proximal colon driving an acute resolving intestinal inflammation dominated by the presence of macrophages. Notably, these macrophages are characterised by their expression of RELMĪ± during the resolution phase of the infection. The RELMĪ±+ macrophage phenotype associates with the presence of alternatively activated macrophages and work in other model systems has demonstrated that the balance of classically and alternatively activated macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELMĪ±+ alternatively activated macrophages are associated with the activation of macrophages via the IL4RĪ±. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known how colonic macrophages are activated towards an alternatively activated phenotype. Here, we address this important knowledge gap by using Trichuris muris infection, in combination with transgenic mice (IL4RĪ±fl/fl.CX3CR1Cre) and IL4RĪ±-deficient/wild-type mixed bone marrow chimaeras. We make the unexpected finding that education of colonic macrophages towards a RELMĪ±+, alternatively activated macrophage phenotype during T. muris infection does not require IL4RĪ± expression on macrophages. Further, this independence is maintained even when the mice are treated with an anti-IFNĪ³ antibody during infection to create a strongly polarised Th2 environment. In contrast to RELMĪ±, PD-L2 expression on macrophages post infection was dependent on IL4RĪ± signalling in the macrophages. These novel data sets are important, revealing a surprising cell-intrinsic IL4R alpha independence of the colonic RELMĪ±+ alternatively activated macrophage during Trichuris muris infection