Introduction
Immune Response in Psoriasis
Dysregulation of Cytokine Network Underlies Psoriasis Pathogenesis
Cytokine | Cellular source | Level in psoriasis | Biological effects in psoriasis | Ref. |
---|---|---|---|---|
IL-1β | Activated macrophages, DCs, KCs, and T cells | ↑ lesional skin | - Activates the pro-inflammatory response of KCs | |
- Promotes the formation of perivascular DCs clusters | ||||
- Triggers TH17 cells differentiation | ||||
- Induces proliferation of dermal γδ T cells | ||||
IL-2 | DCs, activated T cells, macrophages | ↑ lesional skin | - T cells survival factor | [34] |
- Promotes T cells differentiation into effector T cells or memory T cells | ||||
IL-4 | Activated TH2 cells, basophils, mast cells, ILC2 | ↓ in psoriatic epidermal T cells | - Promotes TH2 immune response | |
- Suppresses TH1 and TH17 responses | ||||
- Suppresses IL-1β and IL-6 production by KCs | ||||
- Suppresses IL-23 production by DCs and promotes p35 production | ||||
IL-6 | DCs, endothelial cells, KCs, T cells | ↑ lesional skin | - Promotes TH17 cells differentiation | |
↑ serum of psoriasis patients | - Inhibits suppressive functions of Tregs | |||
- Induces angiogenesis by upregulating VEGF production | ||||
IL-7 | Hair follicle KCs | ↑ lesional skin | - Maintains CD4+ and CD8+ skin-resident memory T cells in the epidermis | |
↑ serum of psoriasis patients | ||||
IL-8 (CXCL8) | Neutrophils, KCs | ↑ lesional skin | - Stimulates neutrophil infiltration | |
↑ serum of psoriasis patients | - Induces KCs hyperproliferation | |||
- Stimulates angiogenesis | ||||
IL-9 | TH9 cells and TH22 cells | ↑ lesional skin | - Induces IL-17A production by CD4+ T cells | |
↑ plasma of psoriasis patients | - Stimulates angiogenesis | |||
IL-10 | TH cells, monocytes, macrophages, and DCs | ↓ lesional skin | - Suppresses type 1 inflammation | [50] |
↑ serum of psoriasis patients | - Downregulates IL-8/CXCR2 pathway in epidermal cells | |||
- Reduces KCs proliferation | ||||
IL-11 | Fibroblasts, epithelial cells | ↑ lesional skin | - Reduces T cells infiltration | [51] |
- Polarizes immune response towards type 2 response | ||||
- Reduces KCs proliferation | ||||
IL-12 | Activated DCs, macrophages, monocytes, and B cells | ↑ IL-12p40 and IL-12p70 in lesional skin | - Inhibits the invasion of γδT17 cells | |
↑ serum of psoriasis patients | - Induces protective transcriptional program in KCs limiting skin inflammation | |||
- No changes or decreased level of IL-12p35 | - Induces IFN-γ production by NK cells and T cells | |||
- Promotes differentiation of TH1 cells | ||||
IL-13 | Activated TH2 cells, mast cells, and basophils | ↑ lesional skin | - Functional role in psoriasis is unclear | |
↑ serum of psoriasis patients | ||||
IL-15 | Hair follicle KCs | ⟷ serum of psoriasis patients | - Synergizes with IL-23 to induce IL-17F, IL-17A, and IFN-γ production by T cells | |
- Induces T cells infiltration | ||||
- Stimulates angiogenesis | ||||
IL-16 | KCs | ↑ serum of psoriasis patients | - Promotes recruitment of CD4+ T cells to psoriatic lesions | [56] |
IL-17 | TH17 cells, Tc17 cells, NK cells, γδ T cells, mast cells, neutrophils | ↑ IL-17A, IL-17C, and IL-17F in lesional skin | - Increases the level of LL37 | |
- Promotes secretion of multiple proinflammatory cytokines, including IL-1β, IL-6, GM-CSF, and TNF | ||||
- Upregulates production of chemokines | ||||
- Impairs Tregs suppressive functions | ||||
IL-18 | KCs | ↑ lesional skin | - Promotes infiltration of immune cells in psoriasiform inflammation | |
↑ serum of psoriasis patients | - Upregulates the expression of IL-17 and suppresses the expression of IL-4 in psoriatic skin | |||
IL-19 | KCs | ↑ lesional skin | - Upregulates the expression of inflammatory mediators in KCs | |
↑ serum of psoriasis patients | - Synergizes with IL-17A to induce production of β-defensin, IL-23p19, and TH17- and neutrophil-attracting chemokines | |||
IL-20 | KCs, leukocytes | ↑ lesional skin | - Promotes angiogenesis and chemotaxis | |
↑ serum of psoriasis patients | - Promotes keratinocyte differentiation and activation | |||
- Stimulates production of pro-inflammatory cytokines | ||||
IL-21 | CD4+ T cells, especially TH17 cells | ↑ lesional skin | - Promotes KCs hyperproliferation | |
↑ serum of psoriasis patients | - Promotes and sustains TH17 cells differentiation | |||
- Inhibits Tregs differentiation | ||||
IL-22 | Mast cells, TH22 cells, TH17 cells, Tc cells, NK-T cells, γδ T cells, DCs, macrophages | ↑ lesional skin | - Stimulates KCs hyperproliferation, differentiation, and migration | |
↑ serum of psoriasis patients | - Induces the secretion of pro-inflammatory cytokines | |||
IL-23 | Inflammatory monocytes, mature DCs, KCs | ↑ lesional skin | - Promotes TH17 activation, survival, and pathogenic potential | |
- Activates dermal γδ T cells and promotes their expansion | ||||
- Stimulates antigen presentation by DCs | ||||
- Triggers IFN-γ production | ||||
- Promotes immune cells infiltration to the skin | ||||
- Triggers hyperplasia of KCs | ||||
IL-24 | KCs, monocytes | ↑ lesional skin | - Induces psoriasis-like inflammation | |
IL-25 (IL-17E) | KCs | ↑ lesional skin | - Stimulates pro-inflammatory phenotype and proliferation of KCs | |
- Stimulates infiltration of DCs, macrophages, and γδ T cells to the skin | ||||
IL-26 | TH1 cells, TH17 cells, NK cells | ↑ lesional skin | - Promotes infiltration of neutrophils and CD4+ T cells into the skin | |
- Stimulates angiogenesis | ||||
IL-33 | Epithelial cells, KCs, DCs | ↑ lesional skin | - Promotes pro-inflammatory phenotype of KCs | [83] |
IL-36γ (IL-1FG) | KCs, monocytes, DCs | ↑ lesional skin | - Induces the expression of AMPs and matrix metalloproteinases (MMPs) by KCs | |
- Regulates the recruitment of inflammatory cells and the expansion IL-17–producing γδ T cells in the skin | ||||
IL-37 | Macrophages, effector memory T cells | ↓ lesional skin | - Inhibits the production of inflammatory mediators by KCs | |
IL-38 | KCs | ↓ lesional skin | - Suppresses psoriatic inflammation | |
↓ serum of psoriasis patients | - Suppresses pro-inflammatory phenotype of KCs | |||
- Suppresses IL-17A production by dermal γδ T cells | ||||
IFN-α | pDCs | ↑ lesional skin | - Induces TH1 and TH17cells and their activation and proliferation | |
↑ serum of psoriasis patients | - Activates DCs and KCs | |||
IFN-β | KCs, pDCs | ↑ lesional skin | - Regulates KCs differentiation | |
- Promotes DCs activation and differentiation | ||||
IFN-γ | T cells, NK cells | ↑ lesional skin | - Activates KCs | |
↑ serum of psoriasis patients | - Promotes T cells infiltration | |||
- Promotes DCs maturation | ||||
TGF-β | Tregs | ↑ lesional skin | - Inhibits KCs proliferation | |
↑ serum of psoriasis patients | - Promotes T cell infiltration | |||
TNF-α | Activated T cells, DCs, macrophages, KCs, fibroblasts | ↑ lesional skin ↑ serum of psoriasis patients | - Activates T cells, macrophages and DCs | |
- Activates KCs triggering hyperproliferation | ||||
- Synergizes with IL-17A | ||||
- Promotes secretion of pro-inflammatory cytokines | ||||
- Induces infiltration of immune cells to the lesional skin | ||||
- Promotes angiogenesis by inducing VEGF secretion |
Chemokines and Homing Receptors Regulate Immune Cell Trafficking in Psoriasis
Chemokine | Receptor | Biological effects in psoriasis | Level in psoriasis | Ref. |
---|---|---|---|---|
CCL2/MCP-1 | CCR2, CCR4 | - DCs and Langerhans cells chemotaxis to the skin | ↑ CCR2 in lesional skin | |
- CCR4 is a skin-homing receptor | ↑ CCR4 in T cells in peripheral blood and psoriatic skin lesions | |||
↑ CCL2 in lesional skin and serum | ||||
↑ CCL2 in KCs by TNF-α and IFN-γ | ||||
CCL3/MIP-1α | CCR1, CCR5 | - TH1 cells, DCs, and monocytes chemotaxis to the skin | ↑ CCL3 in lesional skin | |
- CCR5 regulates lymphocyte detention in the dermis | ↑ CCR5 in lesional skin | |||
↑ CCR5+ T cells and macrophages in the dermis of lesional skin | ||||
CCL4/MIP-1β | CCR1, CCR5 | - TH1 cells, DCs, and monocytes chemotaxis to the skin | ↑ CCL4 in lesional skin | |
CCL5/RANTES | CCR1, CCR3, CCR5 | - TH1 cells and monocytes chemotaxis to the skin | ↑ CCL5 in lesional skin | |
↑ CCL5 in the KCs in lesional skin | ||||
↑CCL5 by IFN-α | ||||
CCL19/MIP-3 β | CCR7 | - T cells and DCs chemotaxis to the lymph nodes, regulation of dermal lymphoid-like tissue | ↑ CCL19 in lesional skin | [131] |
↑ CCR7 in lesional skin | ||||
CCL20/MIP-3α | CCR6 | - TH17 cells, γδ T cells, DCs, and LCs chemotaxis to the skin | ↑ CCL20 in lesional skin | |
↑ CCL20 in KCs by IFN-γ, IL-17A, and IL-22 | ||||
↑ CCL20 in KCs, melanocytes, and dermal endothelial cells by TNF-α and IL-1β | ||||
↑ CCR6+ T cells in lesional skin | ||||
↑ CCR6 by TH17 cytokines | ||||
CCL21/SLC | CCR7 | - T cells and DCs chemotaxis to the lymph nodes | ↓ CCL21+ vessels in psoriatic skin | [135] |
CCL18/PARC | CCR8 | - CD4+ and CD8+ T cells chemotaxis | ↑ CCL18 in lesional skin | [136] |
CCL27/CTACK | CCR10 | - CLA+ T cells chemotaxis | ↓ CCL27 in lesional skin | |
↑ CCL27 in serum of psoriasis patients | ||||
↑ CCR10 in T cells in psoriatic lesions | ||||
↑ CCL27 in KCs by TNF-α and IL-1β | ||||
CXCL1/GRO-α | CXCR2 | - Neutrophils chemotaxis to the skin | ↑ CXCR2 in psoriatic KCs | [139] |
CXCL5/ENA78 | CXCR2 | - Neutrophils chemotaxis to the skin | ↑CXCL5 in the serum of psoriasis patients | |
↑ CXCR2 in psoriatic KCs | ||||
CXCL9/MIG | CXCR3 | - T cells chemotaxis | ↑ CXCL9 in lesional skin | |
↑ CXCR3 in lesional skin | ||||
↑ CXCR3 in epidermal T cells, macrophages, and pDCs in lesional skin | ||||
CXCL10/IP-10 | CXCR3 | - T cells chemotaxis | ↑ CXCL10 in lesional skin, especially in KCs | |
CXCL11/I-TAC | CXCR3 | - T cells chemotaxis | ↑ CXCL11 in lesional skin | |
↑ CXCL11 by IFN-α | ||||
CXCL12/SDF-1 | CXCR4, CXCR7 | - Neutrophils, monocytes, T cells, and DCs chemotaxis | ↑ SDF-1 in lesional skin | [142] |
↑ CXCR4 in lesional skin | ||||
CX3CL1 | CX3CR1 | - Migration and adhesion of leukocytes | ↑ CX3CL1 in endothelial cells and KCs in lesional skin | [143] |
↑ CX3CL1 by TNF-α and IFN-γ | ||||
↑ CX3CR1 in T cells in lesional skin |
Immune Cells in Psoriasis
The Role of Neutrophils
The Role of Monocytes and Macrophages
The Role of Mast Cells
The Role of Innate Lymphoid Cells
The Role of Dendritic Cells
The Role of T cells
TH Cells
TH1 Cells
TH17 Cells
TH22 Cells
TH9 Cells
TH2 Cells
TFH Cells
CD8+Tc Cells
γδ T Cells
T Regulatory Cells (Tregs)
Memory T Cells
T Cells Autoantigens
The Role of B Cells
Non-Immune Cells Regulating Immunity in Psoriasis
The Role of Keratinocytes
The Role of Fibroblasts
The Role of Endothelial Cells
Insights Into the Immune Network in Psoriasis from “Omics” Studies
Reference | Samples | Number of patients | Methodology | Main results |
---|---|---|---|---|
Mehta et al. [163] | Lesional and non-lesional skin | n = 20 | High-dimensional flow cytometry | - CD11c+HLA-DR+ myeloid cells, CD64brightCD163−CD14brightCD1c−CD1a− inflammatory monocytes are the main source of IL-23 |
- CD4+CD49a− CD103− T cells and CD8+ TRM cells produce IL-17A and are PD-1+ | ||||
- IL-23p19 and IL-17A inhibitors reduced IL-23+ myeloid cells | ||||
Guo et al. [290] | Peripheral blood of patients with psoriasis | n = 38 and 30 HC | High-dimensional single-cell mass cytometry | - Identification of new cell subsets abundant in psoriasis CD3– CD4+ lymphoid tissue inducer cells, Tc17 cells, and CD8+ CXCR3+ Tregs |
- CD3− CD4+ cells have high OX40 levels, decreased FRA2 expression, and correlate with the clinical severity | ||||
Farrera et al. [291] | Peripheral blood of patients with psoriasis | n = 19 and 9 HC | High-dimensional single-cell mass cytometry | - Decreased frequency of circulating mucosal-associated invariant T (MAIT) cells |
- Increased frequency of circulating memory Treg cells | ||||
Fyhrquist et al. [292] | Lesional skin from psoriasis patients | n = 134 and 126 HC | cDNA microarrays | - Upregulation of Interferon signaling, LPS-IL-1-mediated inhibition of RXR function, the inflammasome pathway, and TH17 signaling |
- Enrichment of leukocyte activation genes | ||||
- Upregulation of inflammatory mediators (S100 proteins, defensins, matrix metalloproteinases, IL-1 family cytokines), T helper-related genes (CCL1, CCL18, IL17A, IL22, PI3/Elafin), barrier genes (KRT16, SERPINB4, KLK9, FLG2, LCE5A, CLDN8), and genes involved in metabolism of tryptophan | ||||
Li et al. [28] | Lesional skin from patients with psoriasis | n = 92 and 82 HC | Bulk-tissue RNA-seq | - Expression of modules of epidermal differentiation genes |
- Enriched lymphoid and myeloid signature and IL-17-induced genes in KCs | ||||
Nattkemper et al. [293] | Lesional and non-lesional skin from patients with psoriasis | n = 25 and 30 HC | Bulk-tissue RNA-seq | - Identification of “itchscriptome”—upregulated genes associated with itch intensity (phospholipase A2 IVD, substance P, voltage-gated sodium channel 1.7, and transient receptor potential (TRP) vanilloid 1) |
He et al. [294] | Tape strips obtained from lesional and non-lesional skin from patients with psoriasis | n = 20 and 20 HC | RNA-seq | - Increased levels of DCs and T cell markers |
- Increased levels of TH17-related, TH1-related, TH22-IL-22-related, and innate immunity-related genes | ||||
- Downregulated levels of markers of terminal differentiation, tight junction, and lipid biosynthesis and metabolism | ||||
Tsoi et al. [60] | Lesional and non-lesional skin from patients with psoriasis | n = 28 and 38 HC | Bulk-tissue RNA-seq | - Enrichment in the genes associated with immunologic response, IFN, and cytokine signaling pathways |
- Enrichment in the genes associated with MHC class I—antigen processing/presentation, cell-cycle, and arginine/proline metabolism | ||||
- Enrichment in the genes associated with keratinocyte differentiation and cytokine activity in non-lesional skin in psoriatic patients | ||||
Tsoi et al. [295] | Lesional and non-lesional skin from patients with psoriasis treated with etanercept | n = 42 | Bulk-tissue RNA-seq | - The profile of gene expression, including USP18 and KRT2, at baseline of nonlesional psoriatic skin is associated with response to therapy |
Swindell et al. [296] | Meta-analysis of RNA-seq performed from lesional and non-lesional skin from patients with psoriasis | n = 44 | Bulk-tissue RNA-seq | - Induction of psoriasis-specific dysregulated genes by IL-17A |
- Induction of non-specific dysregulated genes by IFN-γ and TNF-α | ||||
- Circulating immune cells share expression signature with other autoimmune diseases | ||||
Nakamizo et al. [297] | Cells isolated by fluorescence-activated cell sorting from dissociated skin tissue | n = 2 and 2 HC | Index-sorted single-cell flow cytometry and RNA sequencing | - Identification of CD14+ type 3 DCs enriched in psoriatic skin and co-producing IL-1B and IL-23A |
Gao et al. [298] | Dermis and epidermis of patients with psoriasis vulgaris | n = 3 and 3 HC | Single-cell RNA-seq | - Upregulation of MHC complex molecules |
- Upregulation of interferon signaling neutrophil modulation, cytokine, and chemokine production | ||||
Kim et al. [299] | Cells isolated by fluorescence-activated cell sorting from dissociated skin tissue | n = 1 | Single-cell RNA-seq | - Increased frequency of lymphocytes and myeloid cells in relapsing area after anti-IL-17A therapy |
- Enrichment of TRM in relapsing psoriasis | ||||
- Upregulation of T17 signature, lipid metabolism maintaining TRM homeostasis, NF-κB signaling, and CXCL13 in lymphoid cells from relapsing psoriasis | ||||
Kim et al. [206] | Cells emigrating from punch biopsy skin | n = 13 and 5 HC | Single-cell RNA-seq | - Identification of cutaneous T17 cells |
- Identification of regulatory IL-10-expressing semimature DCs and a subset of semimature DCs expressing IL-23A and IL-36G | ||||
- Impairment of CCL27-CCR10 interaction due to decreased CCL27 expression in basal KCs | ||||
Cheng et al. [182] | Cells isolated by fluorescence-activated cell sorting from dissociated skin tissue | n = 3 and 3 HC | Single-cell RNA-seq | - Inflammatory response of KCs as well as melanocytes and immune cells |
- High plasticity of cell transcriptional identities of KCs | ||||
- Enrichment of CD1c+CD301A+ DCs | ||||
Zhang et al. [300] | Lesional skin-infiltrating and circulating immune cells | n = 10 | Single-cell RNA-seq and single-cells TCR-seq | - Clonal expansion of CD8+ TEM cells in lesional skin and circulation |
- Strong chemotaxis and cytotoxic signature of T cells in lesional skin | ||||
- Activation of antiviral responses in macrophages | ||||
Liu et al. [301] | CD45 + cells isolated from skin | n = 8 and 7 HC | Single-cell RNA-seq | - Dysregulation of skin-resident memory T cells |
Reynolds et al. [164] | Cells isolated by fluorescence-activated cell sorting from dissociated skin tissue | n = 3 and 5 HC | Single-cell RNA-seq of sorted cell populations | - Clonal expansion of disease-associated lymphocytes |
- Reemergence of prenatal vascular endothelial cell and macrophages cellular programs | ||||
Liu et al. [218] | Sorted CD8+ T cells from lesional skin biopsies | n = 11 and 5 HC | Single-cell RNA-seq of sorted CD8+ T cells | - Identification of 11 CD8+ T cells subset |
- Identification of two non-exhausted Tc17 subsets expressing CXCL13 characterized by upregulated cytokine, cytolytic and metabolic transcriptional activity and associated with disease severity | ||||
Roesner et al. [253] | Lesional and peripheral blood T cells | n = 10 | TCR sequencing of T cells | - T cell repertoires of lesional skin are mirrored by CLA+ circulating T cells |
- Identification of frequent T cell clones within CLA− T cells | ||||
Harden et al. [254] | Lesional and non-lesional skin from patients or healthy controls | n = 8 and 7 HC | High-throughput deep sequencing of TCR | - T cell repertoire in psoriasis is polyclonal |