As an example of incompetent design, this mechanism, discovered by researchers based at the University of California San Diego (UCSD) Medical School, takes some beating. As an example of what a mindless, utilitarian, natural process would come up with, it is entirely understandable, even predictable.
The mechanism in question is that for protecting us from the harmful organisms Creationism's putative intelligent [sic] designer reputedly designed to make us sick. As though that added and unnecessary level of complexity wasn't bad enough, it has had to be switched off to prevent the skin being constantly inflamed, with yet more complexity.
It might sound like a good idea to have a mechanism for stopping your skin being constantly inflamed, but not when you consider the reason it was necessary in the first place. It is the equivalent of a car maker designing iron cladding on the car's rubber tyres to prevent them being punctured by the tacks and spikes he built into the surface of the roads to puncture the rubber tyres, then inventing another rubber tyre to cover the iron cladding to stop the car shaking to pieces - an act of sheer malevolence for which he had to invent a solution, followed by more malevolence and yet another layer of added complexity to compensate for it!
We have figured out why we tolerate certain microbes living on our skin, while the same bacteria would make us very sick if exposed elsewhere in the body. In our research, we identified enzymes that act on the chromosome of specific skin cells that provide immune tolerance by the skin.
Without these enzymes telling our cells to ignore certain bacteria, we’d have a constant rash on our skin.
This is a completely new way to think about skin immune regulation. Through alterations in HDAC activity, we’ve provided a possible way to explore and quiet down unnecessary inflammation by working with skin cells themselves. In the future, drugs designed to turn these enzymes on or off could help treat skin disease as an alternative to antibiotics.
But, if you believe in Creationism's intelligent [sic] designer and the notion of intelligent design as the best explanation for life on Earth, this is what you believe it did, according to a paper by a team of scientists based at the University of California San Diego School of Medicine.Without these enzymes telling our cells to ignore certain bacteria, we’d have a constant rash on our skin.
This is a completely new way to think about skin immune regulation. Through alterations in HDAC activity, we’ve provided a possible way to explore and quiet down unnecessary inflammation by working with skin cells themselves. In the future, drugs designed to turn these enzymes on or off could help treat skin disease as an alternative to antibiotics.
Richard Gallo, MD, PhD, Lead author
Ima Gigli Distinguished Professor of Dermatology,
Department of Dermatology,
UC San Diego School of Medicine.
Ima Gigli Distinguished Professor of Dermatology,
Department of Dermatology,
UC San Diego School of Medicine.
The cells in our body normally respond to the presence of potential threat from organisms such as bacteria, fungi and viruses by activating proteins called 'toll-like receptors' (TLRs) which act as signals to our immune system. However, because our skin is constantly bombarded with these organisms, many of which live on the surface, if these TLRs were activated by skin cells, we would have a constant rash and inflammation, and the other functions of the skin, such as temperature regulation, would not work properly.
So, as a utilitarian work-around to that problem the defence mechanism would otherwise cause, the skin cells have two enzymes called histone deacetylases (HDACs) which inhibit these responses. The UCSD team identified two of these HDACs, HDAC8 and HDAC9.
Ironically, the mechanism for activating these HDACs depends on the organisms themselves acting on the epigenetic settings of the skin cell genome, and the epigenetic system is only necessary because, if you believe this stuff, the intelligent [sic] designer blundered when it used the same cell replication method for the cells of
This is one of the first demonstrations of how the microbiome can interact with epigenetic factors in the skin and modulate the skin’s behavior through the inflammatory response. Whatever environment we’re facing can change a person’s specific response to it. Since this epigenetic change is reversible, unlike alterations to our DNA, we can potentially control our skin inflammatory response through targeting of these enzymes.
multicellular organisms that it used for single-celled organisms, so all the cells get the full genome, regardless of how few genes they need to perform their specialised function - and the advantage of multicellularity is that it allows for division of labour aand speciality. Having given the cells far more genes than they need with all the attendant risks of replicating the entire genome every time, the intelligent [sic] designer then had to come up with a ludicrously complex mechanism for switching most of it off.George Sen, PhD, Co-author
Associate professor of dermatology and cellular and molecular medicine
UC San Diego School of Medicine
Associate professor of dermatology and cellular and molecular medicine
UC San Diego School of Medicine
It now exploits that mechanism to prevent its solution to the problem it caused with its pathogenic organisms from stopping our skin from functioning.
The research team's findings were published a few days ago in Science Immunology:
Cutaneous chaos control by HDACsAnd if you think that is an example of intelligent design, then you must be using private definitions of the words 'intelligent' and 'design'. You might just get away with describing it as the actions of an incompetent, amnesiac, malevolence, if only you could come up with definitive evidence that such an entity exists, a plausible explanation for how it self-assembled out of nothing and a coherent mechanism for how it makes chemistry and physics do things they couldn't do without it. As it is, the childish notion of intelligent design, for no better reason than that your mummy and daddy believed in it, must be one of the most ludicrous ever dreamed up by the Discovery Institute. When examined in detail, almost everything in nature refutes the ideas of intelligence, direction and design.
The skin’s epidermal surface is routinely exposed to a diverse mix of physical, chemical, and microbial stimuli with proinflammatory potential. Epidermal keratinocytes have an innate tendency to tolerate this maelstrom by relying on the histone deacetylases HDAC8 and HDAC9 to restrain signaling pathways that can amplify local inflammation. Sawada et al. used transcriptomic profiling of human keratinocytes activated by poly I:C, a dsRNA mimic, to identify the kinase MAP2K3 as a pivotal target for regulation by HDAC8/9. Inhibition or silencing of HDAC8 or HDAC9 increased expression of MAP2K3 and activation of its downstream target p38MAPK. These findings provide a deeper understanding of how skin inflammation is normally held in check and pinpoint two kinases as potential targets for therapeutic inhibition in inflammatory skin diseases.
Abstract
The skin typically tolerates exposure to various microbes and chemicals in the environment. Here, we investigated how the epidermis maintains this innate immune tolerance to stimuli that are recognized by Toll-like receptors (TLRs). Loss of tolerance to TLR ligands occurred after silencing of the histone deacetylases (HDACs) HDAC8 and HDAC9 in keratinocytes. Transcriptional analysis identified MAP2K3 as suppressed by HDAC8/9 activity and a potential key intermediary for establishing this tolerance. HDAC8/9 influenced acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter. Proteomic analysis further identified SSRP1 and SUPT16H as associated with HDAC8/9 and responsible for transcriptional elongation of MAP2K3. Silencing of MAP2K3 blocked the capacity of HDAC8/9 to influence cytokine responses. Relevance in vivo was supported by observations of increased MAP2K3 in human inflammatory skin conditions and the capacity of keratinocyte HDAC8/9 to influence dendritic cell maturation and T cell proliferation. Keratinocyte-specific deletion of HDAC8/9 also increased inflammation in mice after exposure to ultraviolet radiation, imiquimod, or Staphylococcus aureus. These findings define a mechanism for the epidermis to regulate inflammation in the presence of ubiquitous TLR ligands.
Sawada, Yu; Nakatsuji, Teruaki; Dokoshi, Tatsuya; Kulkarni, Nikhil Nitin; Liggins, Marc C.; Sen, George; Gallo, Richard L.
Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9
Science Immunology 21 May 2021: Vol. 6, Issue 59, eabe1935 DOI: 10.1126/sciimmunol.abe1935
Copyright © 2021 The Authors.
Published by the American Association for the Advancement of Science Reprinted with kind permission under licence #5075301041237
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