John J. Voorhees’s research while affiliated with Concordia University Ann Arbor and other places

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To refine the genetic map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 46 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Skin ageing is an inevitable phenomenon with several characteristic manifestations. The genetic, molecular, and cellular factors that contribute to aged skin are becoming increasingly understood. As our knowledge of how skin ages advances, the potential therapeutic opportunities for skin rejuvenation are similarly increased and improved. In this chapter, the process of skin ageing based on both intrinsic factors and extrinsic influences across the spectrum of skin types is discussed. The biological mechanisms that contribute to these phenomena are further discussed, as well as the progress and opportunities for therapeutic interventions.

In photoaged human skin, type I collagen fragmentation impairs dermal extracellular matrix (ECM) integrity, resulting in collapsed/contracted fibroblasts with reduced type I procollagen synthesis. Injections of cross‐linked hyaluronic acid (CL‐HA) reverse these deleterious changes. To investigate the time course and effects of biochemical changes induced by injected CL‐HA, particularly whether fibroblast activation leads to accumulation/deposition of dermal collagen, we injected CL‐HA into photoaged skin of human participants over 60 years‐old and performed biochemical/microscopic analyses of skin samples. Beginning 1 week post‐injection and lasting 6–9 months, fibroblasts exhibited activation, including increased immunostaining and gene expression of markers of type I collagen synthesis, such as heat shock protein 47 and components of the transforming growth factor‐β pathway. At 1 week post‐injection, multiphoton microscopy revealed elongation/stretching of fibroblasts, indicating enhanced dermal mechanical support. At 4 weeks, second‐harmonic generation microscopy revealed thick collagen bundles densely packed around pools of injected CL‐HA. At 12 months, accumulation of thick collagen bundles was observed and injected CL‐HA remained present in substantial amounts. Thus, by occupying space in the dermal ECM, injected CL‐HA rapidly and durably enhances mechanical support, stimulating fibroblast elongation and activation, which results in thick, densely packed type I collagen bundles accumulating as early as 4 weeks post‐injection and continuing for at least a year. These observations indicate that early and prolonged clinical improvement following CL‐HA injection results from space‐filling and collagen deposition. As type I collagen has an estimated half‐life of 15 years, our data provide the foundations for optimizing the timing/frequency of repeat CL‐HA injections.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Background Multiple treatment options are available for the management of psoriasis, but clinical response varies among individual patients and no biomarkers are available to facilitate treatment selection for improved patient outcomes. Objectives To utilize retrospective data to conduct a pharmacogenetic study to explore the potential genetic pathways associated with drug response in the treatment of psoriasis. Methods We conducted a retrospective pharmacogenetic study using self-evaluated treatment response from 1942 genotyped patients with psoriasis. We examined 6 502 658 genetic markers to model their associations with response to six treatment options using linear regression, adjusting for cohort variables and demographic features. We further utilized an integrative approach incorporating epigenomics, transcriptomics and a longitudinal clinical cohort to provide biological implications for the topmost signals associated with drug response. Results Two novel markers were revealed to be associated with treatment response: rs1991820 (P = 1.30 × 10–6) for anti-tumour necrosis factor (TNF) biologics; and rs62264137 (P = 2.94 × 10–6) for methotrexate, which was also associated with cutaneous mRNA expression levels of two known psoriasis-related genes KLK7 (P = 1.0 × 10–12) and CD200 (P = 5.4 × 10–6). We demonstrated that KLK7 expression was increased in the psoriatic epidermis, as shown by immunohistochemistry, as well as single-cell RNA sequencing, and its responsiveness to anti-TNF treatment was highlighted. By inhibiting the expression of KLK7, we further illustrated that keratinocytes have decreased proinflammatory responses to TNF. Conclusions Our study implicates the genetic regulation of cytokine responses in predicting clinical drug response and supports the association between pharmacogenetic loci and anti-TNF response, as shown here for KLK7.

The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2⁺ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2⁺ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2⁺ myeloid cells, CCR7⁺LAMP3⁺ dendritic cells, and CXCR4 expressed on both CD8⁺ Tc17 cells and keratinocytes, respectively. The SFRP2⁺ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.