Mass cytometry analysis of blood immune cells from psoriasis patients on biological therapy

Solberg, Silje Michelsen; Aarebrot, Anders Krogh; Sarkar, Irene; Petrović, Aleksandra; Sandvik, Lene F; Bergum, Brith; Jönsson, Roland; Bryceson, Yenan T.; Appel, Silke

doi:10.1002/eji.202048857

Cited by 11 publications

(5 citation statements)

References 65 publications

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“…In recent studies, methotrexate has been found to decrease Th17, Th1 cell percentages in blood and restore Treg populations and their immunosuppressive function in patients with psoriasis [ 39 , 40 ]. Also, small molecule and biologic therapies have been shown to increase Th2, Treg cell populations and decrease Th1, Th9, and Th22 cells in blood of patients after treatment [ 12 , 41 ]. Previously, our group has demonstrated that apremilast, a phosphodiesterase 4 inhibitor successfully used for the treatment of the disorder, increases IL-10 producing regulatory B cells and decreases IFNγ and IL-17 producing pro inflammatory T subsets in psoriasis and psoriatic arthritis patients [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

A sharp decrease of Th17, CXCR3+-Th17, and Th17.1 in peripheral blood is associated with an early anti-IL-17-mediated clinical remission in psoriasis

Tsiogkas

Mavropoulos

Dardiotis

et al. 2022

Clinical and Experimental Immunology

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Psoriasis—an immune-mediated skin disease—implicates in its pathophysiology circulating pro-inflammatory cell populations, cytokines, and their interactions with epidermis. The direct effect of approved anti-interleukin- (IL-)17A and anti-IL-17R biologic therapy on immunophenotyping of peripheral blood mononuclear lymphocytes’ (PBMCs) relative sub-population frequencies in psoriasis patients has not yet been described. Using multiparameter flow cytometry we examined T cell subpopulations characterized by CCR6, CCR4 and CXCR3 chemokine receptor surface expression at baseline and after initiation of biologic therapy in PBMCs collected from 30 psoriasis patients. Increased CD3 +CD4 +CXCR3 +, CD3 +CD4 +CCR6 +CCR4 +CXCR3 + (CXCR3 +-Th17) and CD3 +CD4 +CCR6 +CCR4 -CXCR3 + (Th17.1) cell populations were observed in patients with psoriasis in comparison to healthy individuals (n=10). IL-17 therapeutic blockade decreased CD3 +CD4 +CCR6 +, CD3 +CD4 +CXCR3 +, CD3 +CD4 +CCR6 -CXCR3 + (Th1), CD3 +CD4 +CCR6 +CCR4 + (Th17), CD3 +CD4 +CCR6 +CCR4 +CXCR3 + (CXCR3 +-Th17) and CD3 +CD4 +CCR6 +CCR4 -CXCR3 + (Th17.1) cell populations in responding psoriasis patients. Moreover, CD3 +CD4 -CCR6 +, CD3 +CD4 -CXCR3 +, CD3 +CD4 -CCR6 +CCR4 + (Tc17) and CD3 +CD4 -CCR6 -CXCR3 + (Tc1) percentages were also inhibited. Modulation of the same cell sub-populations was also assessed in patients treated with methotrexate (n=4), apremilast (n=4) and anti-IL-23 biologic treatment (n=4). In our study the levels and functional capacity of peripheral pro-inflammatory Th1, Th17 and additional CCR6 + T cell sub-gated populations from psoriasis patients that were treated with anti-IL-17 or anti-IL-17R targeted biologic therapy were explored for the first time. Our data clearly demonstrate that early anti-IL-17 mediated clinical remission is accompanied by a significant decrease of Th1, Th17, CXCR3 +-Th17, and Th17.1 cells.

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Section: Discussionmentioning

confidence: 99%

A sharp decrease of Th17, CXCR3+-Th17, and Th17.1 in peripheral blood is associated with an early anti-IL-17-mediated clinical remission in psoriasis

Tsiogkas

Mavropoulos

Dardiotis

et al. 2022

Clinical and Experimental Immunology

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“…The use of CyTOF technology allowed us to profile the T cell landscape in psoriasis patients comprehensively. Consistent with previous studies (Guo et al, 2019;Solberg et al, 2021), we observed significant alterations in the T cell repertoire of psoriasis patients compared to healthy individuals. The profound differences in T cell subsets and their metabolic states emphasize the systemic nature of psoriasis and provide valuable insights into the pathogenesis of the disease.…”

Section: Discussionsupporting

confidence: 92%

Metabolic crosstalk between keratinocytes and immune cells: new therapeutic options for psoriasis treatment

Wang

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Psoriasis is a complex autoimmune disease characterized by dysregulated interactions between keratinocytes and immune cells. Over the past decade, various antimicrobial peptides, chemokines, and cytokines have been discovered as key mediators in the interplay between keratinocytes and immune cells. These discoveries contribute to the development and application of biologics in the treatment of psoriasis patients. The thickened skin lesions in psoriasis likely represent a resource-limited microenvironment and, how different cells manage resource allocation is a critical question. Hence, different cells need to reprogram their metabolic patterns and establish beneficial metabolic crosstalk to coexist. However, our understanding of the metabolic reprogramming of keratinocytes and their metabolic crosstalk with other cell types in psoriasis is still limited. To address these issues, in Chapters 2 and 3, we first studied the miR-31-induced metabolic reprogramming in keratinocytes, which was found to enhance glutamine metabolism and promote the secretion of immune molecules and metabolites. The composition of these secreted substances facilitate the differentiation of CD4+ naïve T cells into Th17 cells. Especially, aspartate was found to enhance Th17 cell differentiation induced by IL-6 and TGFβ, by upregulating glycolysis to sustain the malate aspartate shuttle (MAS) and increase oxidative phosphorylation of Th17 cells. Subsequent in vitro and in vivo experiments demonstrated that targeting GLS (inhibiting glutaminolysis), SLC1A3 (blocking aspartate uptake), or GOT1 (inhibiting aspartate metabolism) can reduce Th17 cell differentiation and alleviated skin inflammation in a mouse model of psoriasis. Notably, aspartate was found elevated in the serum of psoriasis patients. In addition, the psoriasis-derived CD4+ naïve T cells expressed high levels of GOT1 and MDH1 and increased the aspartate and glutamate metabolism pathway as compared to those from healthy subjects. Collectively, our in vitro and in vivo results demonstrate that highly expressed miR-31 in keratinocytes can influence the local and systemic metabolic environment and build metabolic crosstalk with immune cells to amplify the inflammatory feedback loop in psoriasis. In Chapter 4, we demonstrate that the metabolites in the serum of psoriasis patients mediate crosstalk between different types of immune cells upon treatment with Methotrexate. These findings highlight the pervasive presence of metabolic crosstalk and its significant contribution to the therapeutic effects of methotrexate in treating psoriasis. In Chapter 5, we show that PSORI-CM02, a Chinese herbal formula that is used clinically in the treatment of psoriasis, effectively reduced HK2 expression and attenuated glycolysis in keratinocytes through the mTOR pathway. In conclusion, we uncovered the metabolic reprogramming of psoriasis keratinocytes and their metabolic crosstalk with CD4+ naïve T cells. We also provided initial insights into the therapeutic potential of targeting either the glutamine-dependent differentiated keratinocytes or the glucose-dependent proliferating keratinocytes, as well as blocking the aspartate-dependent metabolic crosstalk between keratinocytes and CD4+ naïve T cells. These studies have expanded our understanding of the interaction mechanisms between keratinocytes and immune cells, introducing metabolites such as aspartate as novel mediators and offering new strategies for the treatment of psoriasis.

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“…CD4 + T helper (T H ) cells orchestrate skin inflammation in psoriasis [ 195 ]. Both skin-infiltrating and circulating T H cells in psoriasis are predominantly T H 1, T H 9, T H 17, and T H 22 cells [ 70 , 197 ].…”

Section: Immune Cells In Psoriasismentioning

confidence: 99%

The Immunology of Psoriasis—Current Concepts in Pathogenesis

Sieminska,

Pieniawska,

Grzywa

2024

Clinic Rev Allerg Immunol

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Psoriasis is one of the most common inflammatory skin diseases with a chronic, relapsing-remitting course. The last decades of intense research uncovered a pathological network of interactions between immune cells and other types of cells in the pathogenesis of psoriasis. Emerging evidence indicates that dendritic cells, TH17 cells, and keratinocytes constitute a pathogenic triad in psoriasis. Dendritic cells produce TNF-α and IL-23 to promote T cell differentiation toward TH17 cells that produce key psoriatic cytokines IL-17, IFN-γ, and IL-22. Their activity results in skin inflammation and activation and hyperproliferation of keratinocytes. In addition, other cells and signaling pathways are implicated in the pathogenesis of psoriasis, including TH9 cells, TH22 cells, CD8+ cytotoxic cells, neutrophils, γδ T cells, and cytokines and chemokines secreted by them. New insights from high-throughput analysis of lesional skin identified novel signaling pathways and cell populations involved in the pathogenesis. These studies not only expanded our knowledge about the mechanisms of immune response and the pathogenesis of psoriasis but also resulted in a revolution in the clinical management of patients with psoriasis. Thus, understanding the mechanisms of immune response in psoriatic inflammation is crucial for further studies, the development of novel therapeutic strategies, and the clinical management of psoriasis patients. The aim of the review was to comprehensively present the dysregulation of immune response in psoriasis with an emphasis on recent findings. Here, we described the role of immune cells, including T cells, B cells, dendritic cells, neutrophils, monocytes, mast cells, and innate lymphoid cells (ILCs), as well as non-immune cells, including keratinocytes, fibroblasts, endothelial cells, and platelets in the initiation, development, and progression of psoriasis.

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Mass cytometry analysis of blood immune cells from psoriasis patients on biological therapy

Cited by 11 publications

References 65 publications

A sharp decrease of Th17, CXCR3+-Th17, and Th17.1 in peripheral blood is associated with an early anti-IL-17-mediated clinical remission in psoriasis

A sharp decrease of Th17, CXCR3+-Th17, and Th17.1 in peripheral blood is associated with an early anti-IL-17-mediated clinical remission in psoriasis

Metabolic crosstalk between keratinocytes and immune cells: new therapeutic options for psoriasis treatment

The Immunology of Psoriasis—Current Concepts in Pathogenesis

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