Novel, postnatal manifestation of an epidermal barrier defect in a mouse model of isolated sulfite oxidase deficiency

Novel, postnatal manifestation of an epidermal barrier defect in a mouse model of isolated sulfite oxidase deficiency | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Novel, postnatal manifestation of an epidermal barrier defect in a mouse model of isolated sulfite oxidase deficiency Lena Johannes , Matthias Rübsam , Julia Löhr , Xiaolei Ding , Sabine Eming , Carien M. Niessen , Günter Schwarz doi: https://doi.org/10.1101/2024.03.14.584870 Lena Johannes 1 Institute for Biochemistry, Department of Chemistry, University of Cologne , Cologne, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matthias Rübsam 2 Department Cell Biology of the Skin, University Hospital Cologne, University of Cologne 4 Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne Find this author on Google Scholar Find this author on PubMed Search for this author on this site Julia Löhr 2 Department Cell Biology of the Skin, University Hospital Cologne, University of Cologne 3 Cologne Excellence Cluster for Stress Responses in Ageing-associated diseases (CECAD), University of Cologne , Cologne, Germany 4 Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne Find this author on Google Scholar Find this author on PubMed Search for this author on this site Xiaolei Ding 5 University of Cologne Department of Dermatology, University Hospital Cologne , Cologne, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sabine Eming 3 Cologne Excellence Cluster for Stress Responses in Ageing-associated diseases (CECAD), University of Cologne , Cologne, Germany 4 Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne 5 University of Cologne Department of Dermatology, University Hospital Cologne , Cologne, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: gschwarz{at}uni-koeln.de Carien M. Niessen 2 Department Cell Biology of the Skin, University Hospital Cologne, University of Cologne 3 Cologne Excellence Cluster for Stress Responses in Ageing-associated diseases (CECAD), University of Cologne , Cologne, Germany 4 Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: gschwarz{at}uni-koeln.de Günter Schwarz 1 Institute for Biochemistry, Department of Chemistry, University of Cologne , Cologne, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: gschwarz{at}uni-koeln.de Abstract Full Text Info/History Metrics Preview PDF Abstract Sulfite oxidase deficiency is a rare inborn error in metabolism leading to early childhood death due to rapidly progressing neurodegeneration. A new mouse model of sulfite oxidase deficiency carrying a homozygous deletion in the Suox gene resembles the human pathology in terms of neonatal death and elevation of sulfite and thiosulfate in plasma and urine, respectively. Homozygous Suox -/- mice are initially born healthy, display growth retardation starting at postnatal day 4 and die in average at day 9.6. Here we report that Suox -/- mice develop dry and scaly skin early postnatally, showing that sulfite oxidase is essential to maintain a functional skin barrier after birth. At postnatal day 5 Suox -/- mice develop altered epidermal morphology and dysregulated early and late keratinocyte differentiation accompanied by increased stress response. We propose a sulfite-induced cleavage of disulfide bonds in key epidermal proteins essential for a functional barrier. To the Editor Isolated sulfite oxidase deficiency (SOXD) is a rare metabolic disorder typically presenting with postnatal intractable seizures and progressive neurodegeneration, resulting in infant death if left untreated ( Johnson & Duran, 2001 ). It is caused by a loss of function of the enzyme sulfite oxidase (SOX), which catalyzes the clearance of sulfite via oxidation to sulfate as the final step of cysteine catabolism ( Irreverre et al., 1967 ). A loss in SOX activity results in an accumulation of toxic sulfite and elevated levels of the sulfur metabolites taurine, thiosulfate and S-sulfocysteine. Due to its structural resemblance to glutamate, S-sulfocysteine acts as an NMDA receptor agonist, thus causing vast excitotoxicity and manifestation of a progressive neurological phenotype ( Kumar et al., 2017 ). Recently, a mouse model for SOXD has been successfully established through inactivation of the Suox gene ( Fu et al. 2024 ). Heterozygous animals develop without visible phenotype. Homozygous Suox -/- mice are initially born healthy, but around postnatal day 4 start to display growth retardation and decreased neuromotor abilities, and die between P6 and P12 with an average survival time of 9.6 days. Interestingly, brain morphological analysis shortly before death did not reveal significant abnormalities, thus excluding neurodegeneration as the major cause of death, and indicating additional pathomechanisms and causes of death for Suox -/- mice and human SOXD patients ( Fu et al. 2024 ). Here we report that Suox -/- mice develop dry and scaly skin early postnatally, showing that SOX is essential to maintain a functional skin barrier after birth. Newborn (P0) Suox -/- mice initially displayed normal skin, both macroscopically as well as in H&E stained histological sections of P0 back skin with the epidermis appearing similar to control mice ( Fig. 1A, E ). In agreement, immunofluorescence analysis revealed no change in localization of keratin (K)14 ( Fig. 1B, F ), marking the proliferating basal layer, and K10 ( Fig.1C,G ), a differentiation marker for all suprabasal layers ( Fuchs & Green, 1980 ). Moreover, staining for proliferation marker Ki67 demonstrated similar proliferation between control and Suox -/- newborn mice ( Fig. 1D, H ). Together, these data indicate that the skin develops normally in utero upon loss of SOX enzyme. Download figure Open in new tab Figure 1: (previous page): Suox -/- mice develop altered epidermal morphology and dysregulated early keratinocyte differentiation within the first days of life. (A) H&E stainings of back skin sections of Suox -/- pups from P0 (left) and P5 (right). (B-D) Immunofluorescent stainings of paraffin-embedded back skin sections for (B) basal cell marker Keratin14 (K14), (C) early differentiation marker Keratin10 (K10) and (D) proliferation marker Ki67, each at P0 (left) and P5 (right). (E) Quantification of epidermal thickness (excluding SC). (F) Quantification of K14 thickness. (G) Quantification of K10 intensity. (H) Quantification of ki67-positive cells. Each data point represents one animal, per animal ten microscopic pictures were analyzed, *** P <0.001, *P <0.05 with Student’s t -test. At P5, H&E staining revealed a significant increase in epidermal thickness in homozygous Suox -/- animals ( Fig. 1A, E ). Closer examination indicated that this increase in thickness likely originates from a combination of enlarged cells in the stratum basale (SB) as well as an increase in cell number and layers of the suprabasal spinous layers ( Fig. 1A ). The stratum granulosum (SG) appeared thinner, with a reduced number of granules, while cells in the stratum corneum (SC) showed decreased structural organization and parakeratosis ( Fig. 1A ), suggesting changes in differentiation. In agreement, immunofluorescence analysis revealed a strong increase in suprabasal K14 staining ( Fig. 1B, F ) and a strong reduction in the differentiation marker K10 in suprabasal layers ( Fig. 1C, G ), indicating that cells that moved suprabasally failed to properly differentiate and retain basal identity. In agreement, the proliferation marker Ki67 was increased and no longer confined to the basal layer ( Fig. 1D, H ). To directly confirm that differentiation was altered postnatally, we stained for late differentiation markers involucrin, loricrin and filaggrin. Whereas staining for loricrin was almost absent in P5 Suox -/- skin ( Fig. 2A ), and for filaggrin largely reduced ( Fig. 2B ), involucrin was still similar to control mice ( Fig. 2C ). Furthermore, K6, a stress-induced keratin (Eckhardt et al., 2019), was increased in the intrafollicular epidermis ( Fig. 2D ), providing additional evidence for disturbed differentiation and the presence of stressed keratinocytes. Together, these data indicate that epidermal loss of SOX postnatally promotes proliferation and impairs differentiation, resulting in a morphologically altered barrier. Download figure Open in new tab Figure 2: Suox -/- mice develop dysregulated late keratinocyte differentiation and increased stress response within the first days of life. (A-D) Immunofluorescent stainings of paraffin-embedded back skin sections of control and Suox -/- P5 for structural proteins and late differentiation markers (A) Loricrin, (B) Filaggrin, (C) Involucrin and (D) keratin K6a. (E) Isolated corneocyte appearance. (F) Quantification of corneocyte area, P =0.2258. (G) Quantification of corneocyte perimeter, P =0.0001. (F+G) >300 cells with Kolmogorov-Smirnov (accumulated from Ctr n=4, Suox -/- n=7 biological replicates). (H) Quantification of ruffled corneocytes, ** P =0.0061 with Mann–Whitney test; Ctr n=4, Suox -/- n=7 biological replicates. (I+J) qRT-PCR analysis of stressed barrier (I) and inflammatory (J) genes on RNA isolated from the epidermis of control and Suox -/- P5 mice. *** P <0.001, ** P <0.005, *P <0.05 with Student’s t -test. To investigate whether changes in epidermal terminal differentiation also altered barrier function upon loss of SOX, we isolated corneocytes from P5 mice and examined their appearance ( Fig. 2E ). Although average corneocyte area was still similar ( Fig. 2F ), the average perimeter was somewhat larger ( Fig. 2G ), likely due to an increase in the percentage of corneocytes with less smooth, more ruffled appearance ( Fig. 2H ), showing that the stratum corneum is abnormal and likely less functional. In agreement, real time PCR showed that next to K6 several markers (Slpi, S100a8, and several small proline-rich protein (Sprr) family members) known to be upregulated upon a dysfunctional barrier, were highly increased in Suox -/- mice ( Fig. 2I ), further verifying the impairment of epidermal barrier integrity. Interestingly, Sprr2 upregulation in loricrin -/- mice is thought to compensate and maintain partial barrier function ( Koch et al., 2000 ). Thus, the upregulation of several Sprrs observed here might equally function as an initial compensatory mechanism aiming to try and prevent the formation of a more severe epidermal phenotype. An impaired barrier function often induces an innate inflammatory response. Although quantitative PCR analysis revealed no significant alteration in the expression of most inflammatory genes, Il1b mRNA levels were significantly elevated ( Fig. 2J ), whereas IL6 also showed a tendency for a strong increase. IL-1β was shown to induce the expression of K6a ( Komine et al., 2001 ), while additionally activating transcription factor NF-κB, which can cause the downregulation of filaggrin and loricrin expression ( Michaelidou et al., 2023 ). Moreover, mRNA levels of Tslp , a master regulator of type II skin immunity ( Hasegawa et al. 2022 ), were also vastly elevated ( Fig. 2J ). In humans, cytokine TSLP was found to impair epidermal barrier integrity by upregulating the expression of nuclear cytokine IL-33, which in turn is involved in the downregulation of loricrin, filaggrin and K10 expression ( Dai et al., 2021 , 2022). Thus, the observed overexpression of IL-1β and TSLP presumably contributes to the altered expression patterns of respective marker proteins in our Suox -/- mouse model as well. Overall, our results suggest that late onset differentiation proteins such as the SPRR family together with hyperproliferation may act as a mechanism to counteract the postnatally occurring altered terminal differentiation and subsequent epidermal barrier dysfunction in Suox -/- mice. Notably, our data revealed a variable phenotype, ranging from almost control-like to severely altered epidermal morphology at P5 ( Fig. 1 , 2 ). As the life span of Suox -/- mice typically lies between six and twelve days, the phenotypic severity at P5 may be linked to the age of onset and likely explains the variation in survival days. We therefore propose a progressive, postnatal loss of epidermal barrier integrity due to excessive accumulation of sulfite. SOX shows moderate expression in the skin ( Uhlén et al., 2015 ), but until this report, no role for its regulation in skin homeostasis was ascribed yet. However, sulfite, which accumulates upon SOX deficiency, can act as a nucleophile to cleave disulfide bonds ( Kella & Kinsella, 1985 ). Disulfide bonds are crucial for epidermal barrier integrity, as these are important for the cross-linkage of keratin filaments and other structural proteins such as loricrin, the major component of the cornified cell envelope ( Hohl et al., 1991 ; Suns & Green, 1978 ). In addition, a knock-in mouse model expressing K14 with a single cysteine-to-alanine mutation that reduced disulfide bond formation in the basal K14 protein, displayed changes in Yap- dependent transcription that impaired differentiation and barrier function, including suprabasal K14 expression and decreased K10, filaggrin and loricrin intensity ( Guo et al., 2020 ). Thus, our results indicate that SOX postnatally regulates the extend of disulfide bonds in key epidermal proteins essential for a functional barrier. Further studies will be required to understand the contribution of cysteine modifications and unravel the exact pathomechanism. References Dai , X. , Muto , J. , Shiraishi , K. , Utsunomiya , R. , Mori , H. , Murakami , M. , & Sayama , K. ( 2022 ). TSLP Impairs Epidermal Barrier Integrity by Stimulating the Formation of Nuclear IL-33/Phosphorylated STAT3 Complex in Human Keratinocytes . Journal of Investigative Dermatology , 142 ( 8 ), 2100 – 2108 .e5. doi: 10.1016/J.JID.2022.01.005 OpenUrl CrossRef ↵ Dai , X. , Utsunomiya , R. , Shiraishi , K. , Mori , H. , Muto , J. , Murakami , M. , & Sayama , K. ( 2021 ). Nuclear IL-33 Plays an Important Role in the Suppression of FLG, LOR, Keratin 1, and Keratin 10 by IL-4 and IL-13 in Human Keratinocytes . 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Tissue-based map of the human proteome . Science , 347 ( 6220 ). doi: 10.1126/SCIENCE.1260419/SUPPL_FILE/1260419_UHLEN.SM.PDF OpenUrl CrossRef View the discussion thread. Back to top Previous Next Posted March 19, 2024. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Novel, postnatal manifestation of an epidermal barrier defect in a mouse model of isolated sulfite oxidase deficiency Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. 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