The protease <scp>ADAM17</scp> at the crossroads of disease: revisiting its significance in inflammation, cancer, and beyond

Saad, Mohamed I.; Jenkins, Brendan J.

doi:10.1111/febs.16923

Cited by 11 publications

(10 citation statements)

References 107 publications

(175 reference statements)

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“…Increased expression of inflammatory mediators, such as Adam17 (Figure 4D), an inflammatory protease that cleaves numerous cell membrane cytokines and receptors, including the TAM receptor MERTK (19)(20)(21)(22). Cleavage of MERTK results in reduced phagocytotic clearance of apoptotic cells and pro-inflammatory nucleic acids (19,23,24).…”

Section: Immunolocalization Of Rmpmentioning

confidence: 99%

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Alam,

Yaman,

Silva

et al. 2024

Front. Med.

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BackgroundDry eye causes corneal inflammation, epitheliopathy and sensorineural changes. This study evaluates the hypothesis that dry eye alters the percentages and transcriptional profiles of immune cell populations in the cornea.MethodsDesiccating stress (DS) induced dry eye was created by pharmacologic suppression of tear secretion and exposure to drafty low humidity environment. Expression profiling of corneal immune cells was performed by single-cell RNA sequencing (scRNA-seq). Cell differentiation trajectories and cell fate were modeled through RNA velocity analysis. Confocal microscopy was used to immunodetect corneal immune cells. Irritation response to topical neurostimulants was assessed.ResultsTwelve corneal immune cell populations based on their transcriptional profiles were identified at baseline and consist of monocytes, resident (rMP) and MMP12/13 high macrophages, dendritic cells (cDC2), neutrophils, mast cells, pre T/B cells, and innate (γDT, ILC2, NK) and conventional T and B lymphocytes. T cells and resident macrophages (rMP) were the largest populations in the normal cornea comprising 18.6 and 18.2 percent, respectively. rMP increased to 55.2% of cells after 5 days of DS. Significant changes in expression of 1,365 genes (adj p < 0.0001) were noted in rMP with increases in cytokines and chemokines (Tnf, Cxcl1, Ccl12, Il1rn), inflammatory markers (Vcam, Adam17, Junb), the TAM receptor (Mertk), and decreases in complement and MHCII genes. A differentiation trajectory from monocytes to terminal state rMP was found. Phagocytosis, C-type lectin receptor signaling, NF-kappa B signaling and Toll-like receptor signaling were among the pathways with enhanced activity in these cells. The percentage of MRC1+ rMPs increased in the cornea and they were observed in the basal epithelium adjacent to epithelial nerve plexus. Concentration of the chemokine CXCL1 increased in the cornea and it heightened irritation/pain responses to topically applied hypertonic saline.ConclusionThese findings indicate that DS recruits monocytes that differentiate to macrophages with increased expression of inflammation associated genes. The proximity of these macrophages to cornea nerves and their expression of neurosensitizers suggests they contribute to the corneal sensorineural changes in dry eye.

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Section: Immunolocalization Of Rmpmentioning

confidence: 99%

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Alam,

Yaman,

Silva

et al. 2024

Front. Med.

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“…Second, we developed two distinct including growth factors, cytokines, receptors, and cell adhesion molecules. It plays a pivotal role in intracellular signaling pathways related to inflammation and angiogenesis [52][53][54][55]. By analyzing a publicly available scRNA-seq (Drop-seq) dataset (GSE150703) that compared OIR and normal conditions [56], we observed an increase in Adam17 substrates in rod photoreceptor cells in OIR mice (Fig.…”

Section: Discussionmentioning

confidence: 97%

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos

Wang,

Kaneko

et al. 2024

Angiogenesis

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Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.

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“…Both iRhoms are widely expressed, with two notable exceptions: iRhom1 expression is low or absent in myeloid cells, and iRhom2 expression is low or absent in the brain in mice, except for microglia [ 5 , 12 ]. ADAM17 has important roles in development and disease by regulating the TNFα-, EGFR- and other signaling pathways [ 12 , 13 , 14 , 15 , 16 , 17 ]. Since iRhom2 is required for the activity of ADAM17 in myeloid cells, mice lacking iRhom2 are protected from endotoxin shock and inflammatory arthritis [ 1 , 12 ], like mice lacking ADAM17 in myeloid cells [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation

Azzopardi,

Lu,

Monette

et al. 2024

IJMS

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The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2) modulate cell–cell interactions by mediating the release of membrane proteins such as TNFα (Tumor necrosis factor α) and EGFR (Epidermal growth factor receptor) ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here, we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of more than a thousand OR genes in mice. iRhom2-/- mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in iRhom2-/- OE, OSNs expressing ORs that are enriched in iRhom2-/- OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of an olfactory receptor that is ectopically expressed in keratinocytes (OR2AT4) by its agonist Sandalore leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.

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The protease ADAM17 at the crossroads of disease: revisiting its significance in inflammation, cancer, and beyond

Cited by 11 publications

References 107 publications

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Single cell analysis of short-term dry eye induced changes in cornea immune cell populations

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos

Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation

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