Genomic control of inflammation in experimental atopic dermatitis

Abstract

Atopic Dermatitis (AD) or eczema, a recurrent allergic inflammation of the skin, afflicts 10–20% of children and 5% adults of all racial and ethnic groups globally. We report a new topical treatment of AD by a Nuclear Transport Checkpoint Inhibitor (NTCI), which targets two nuclear transport shuttles, importin α5 and importin β1. In the preclinical model of AD, induced by the active vitamin D3 analog MC903 (calcipotriol), NTCI suppressed the expression of keratinocyte-derived cytokine, Thymic Stromal Lymphopoietin (TSLP), the key gene in AD development. Moreover, the genes encoding mediators of TH2 response, IL-4 and its receptor IL-4Rα were also silenced together with the genes encoding cytokines IL-1β, IL-6, IL-13, IL-23α, IL-33, IFN-γ, GM-CSF, VEGF A, the chemokines RANTES and IL-8, and intracellular signal transducers COX-2 and iNOS. Consequently, NTCI suppressed skin infiltration by inflammatory cells (eosinophils, macrophages, and CD4 + T lymphocytes), and reduced MC903-evoked proliferation of Ki-67-positive cells. Thus, we highlight the mechanism of action and the potential utility of topical NTCI for treatment of AD undergoing Phase 1/2 clinical trial (AMTX-100 CF, NCT04313400).

Activation of thousands of genes in the lungs and kidneys by sepsis is countered by the selective nuclear blockade

“…These two cytoplasmic proteins are required for the nuclear translocation of an entire set of proinflammatory SRTFs and MTFs to the cell’s nucleus. Thus, the NTCI disables the inflammatory and metabolic regulomes thereby silencing (until this study) at least 32 known genes encoding the mediators of inflammation in animal models of allergic ( 62 ), autoimmune, metabolic, microbial, and physical inflammation ( 19 ). In the experimental sepsis model studied by us herein, the number of genes regulated by the selective nuclear blockade in the lungs and kidneys exceeds 3,700 and 1,900, respectively (see the conceptual figure, Figure 5 ).…”

“…The NTCI reported in this and earlier reports, represents a new class of broad-spectrum anti-inflammatory agents for topical (localized) genomic control of inflammation ( 62 ) and, if needed, systemic therapy of sepsis and related diseases mediated by microbial inflammation ( 19 ). Other broad-spectrum anti-inflammatory agents, the glucocorticoids, e.g., dexamethasone, target the inflammatory regulome via the action of the cognate nuclear receptor, which functions as a transcription factor, inducing genomic response ( 66 – 68 ).…”

“…Moreover, the potential adverse impact of inhibiting importin α5 was allied by the report that mice with an importin α5 deficiency are viable and fertile and do not display any apparent morphological and behavioral defects ( 63 ). Significantly, the NTCI inhibits the nuclear translocation of larger transcription factors (MW>45 kDa), such as SRTFs and MTFs by targeting the Imp α5/Imp β1 complex ( 16 , 62 ). Therefore, in the presence of the NTCI, the smaller transcription factors (MW<45 kDa), which are essential to cell survival and maintenance, can freely translocate to the nucleus and contribute to the homeostasis and lifespan of cells treated with the NTCI ( 16 ).…”

“…The NTCI (cSN50.1 aka. AMTX-100 CF) is in the ongoing Phase 2 clinical trial for mild to moderate Atopic Dermatitis (NCT04313400), the most common skin disease ( 62 ).…”

Anti‐inflammatory control of human skin keratinocytes by targeting nuclear transport checkpoint

“…These genes are involved in AD and other human inflammatory skin diseases. 9 Henceforth, we analysed nuclear signalling by TFs at the subcellular level in primary human KCs derived from adult skin to determine whether their broad inflammatory response 2 is mediated by the two acute phase response TFs, NF-κB Rel A and STAT3. 18,19 We reasoned that the NTCI, known to arrest the nuclear translocation of TFs responding to inflammatory stress in immune and non-immune cells, 3 should be similarly effective in cultured human KCs.…”