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more than a skin disease
Psoriasis (PsO) pathology, like that of other autoimmune disorders, is driven by immune and inflammatory signaling pathways.1-3 Many cytokines regulate such signaling cascades by transmitting extracellular signals to intracellular molecules and inducing a chain of events that ultimately leads to inflammatory signal amplification.4,5
Certain extracellular signals are particularly relevant to the pathophysiology of PsO: In particular, Type I interferon (IFN), interleukin (IL)-12, IL-23, IL-17, and tumor necrosis factor-α (TNF-α).3,6−9 Type I IFN plays an important role in the initiation of PsO pathology.6,7 IL-23, IL-17 and IL-12 support the development and perpetuation of PsO, while TNF-α affects both the initiation and the perpetuation phases.3,6,8−10 These and other pro-inflammatory cytokines, including IL-6, interferon-gamma (IFN-γ) and IL-22, play an important role in pathogenic signaling and may contribute to the many co-morbidities associated with PsO.3,6,8
Their functions are listed below:
- Type I IFN is produced by plasmocytic dendritic cells (DCs) in response to anti-microbial peptides and other pro-inflammatory signals from injured or infected keratinocytes.6,12 This signal is received by myeloid and conventional DCs (mDCs, cDCs), stimulating these cells to produce further pro-inflammatory cytokines, such as IL-12 and IL-23.1,13,14
Transduction of extracellular cytokine signals 
Baker KF, Isaacs JD. Ann Rheum Dis. 2018;77:175–187. Morris R et al. Protein Sci. 2018;27:1984–2009.
- IL-12 is produced by DCs activated by type I IFN, and stimulates the differentiation of Th1 cells, which produce a number of pro-inflammatory cytokines that activate keratinocytes and support skin lesion development, including IFN-γ and TNF-α.13
- IL-23 is produced by DCs in response to type I IFN or to TNF-α stimulation, and supports the differentiation of Th17 cells.8,13 IL-23−based activation of Th17 cells and the subsequent release of IL-17 family cytokines and other pro-inflammatory cytokines activates keratinocytes and is a known driver of PsO disease.5 This is known as the “IL-23/IL-17 axis of PsO”.8
- IL-17 family cytokines are a key driver of inflammation in PsO.6,8 A study in ex vivo cultured skin showed that IL-17A, IL-17F, IL-17A/F, and IL-17C are expressed at increased levels in PsO and can induce PsO-related inflammation.15
- TNF-α has long been known to be implicated in PsO pathology, although its exact role in PsO pathogenesis has not been completely elucidated yet.8 The current understanding is that TNF-α is implicated in both the initiation and the chronic phase of the disease by indirectly acting to regulate the IL-23/IL-17 inflammatory axis.8,10 TNF-α, in fact, directly stimulates the production of IL-23 by keratinocytes and DCs, as well as potentiates IL-17 signaling by enhancing pro-inflammatory gene expression in keratinocytes.8,10,16
Psoriasis pathophysiology
AMP, anti-microbial peptide; cDC, conventional dendritic cell; IFN, interferon; IL, interleukin; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; Th, T helper; TYK2, tyrosine kinase 2.
Afonina IS et al. Cell Mol Life Sci. 2021;78:2709-2727. Alwan W, Nestle FO. Clin Exp Rheumatol. 2015;33:S2-S6. Furue M et al. Int J Mol Sci. 020;21:1275. Greb JE et al. Nat Rev Dis Primers. 2016;2:16082. Hawkes JE et al. J Immunol. 2018;201:1605-1613. Nestle FO et al. J Exp Med. 2005;202:135-143. Rendon A, Schäkel K. Int J Mol Sci. 2019;20:1475. Zhang LJ. Front Immunol. 2019;10:1440.
- IL-6 is a pro-inflammatory cytokine released by keratinocytes that adds to the inflammatory cascade in PsO.16
- IFN-γ signaling is released by IL-12−differentiated Th1 cells, along with TNF-α, to activate keratinocytes.13
- IL-22 signaling is primarily secreted by Th17 cells, as well as Th22 cells, to activate keratinocyte proliferation in PsO.13,16,17
A certain level of overlap and shared mechanisms in the cytokine signaling pathways is observed in several co-morbidities of PsO.18−24 For instance, the IL-23/IL-17 axis of inflammation is known to be involved in psoriatic arthritis (PsA): In this condition, IL-23 acts directly to increase inflammation in the synovium while also supporting the differentiation of Th17 cells that release IL-17 and TNF-α to activate synoviocytes and differentiate osteoclasts.18,19 At the same time, IL-22 also acts at tendon insertion points to promote pathologic bone formation in enthesitis.19 In cardiovascular disease, IL-17A may contribute to atherosclerotic lesion progression, and cytokines produced by Th17 cells are associated with deep vein thrombosis.20,21 Cytokines such as IL-17, IFN-γ, and TNF-α play a prominent role in the development of the inflammatory processes that accompany inflammatory bowel disease (IBD), metabolic syndrome (MetS), and non-alcoholic fatty liver disease (NAFLD), among others.22−24
Psoriasis pathophysiology
AMP, anti-microbial peptide; cDC, conventional dendritic cell; IFN, interferon; IL, interleukin; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; Th, T helper; TYK2, tyrosine kinase 2.
Afonina IS et al. Cell Mol Life Sci. 2021;78:2709-2727. Alwan W, Nestle FO. Clin Exp Rheumatol. 2015;33:S2-S6. Furue M et al. Int J Mol Sci. 020;21:1275. Greb JE et al. Nat Rev Dis Primers. 2016;2:16082. Hawkes JE et al. J Immunol. 2018;201:1605-1613. Nestle FO et al. J Exp Med. 2005;202:135-143. Rendon A, Schäkel K. Int J Mol Sci. 2019;20:1475. Zhang LJ. Front Immunol. 2019;10:1440.
Therefore, inflammation is the result of a highly orchestrated chain of extra- and intra-cellular events driven by a broad range of cytokine signals.3,6,8,11−13 Such signaling, and its associated downstream effects, play a crucial role in initiating and maintaining chronic inflammation in PsO as well as other associated co-morbidities.3,6,11,12,18−24
Psoriasis pathophysiology
AMP, anti-microbial peptide; cDC, conventional dendritic cell; IFN, interferon; IL, interleukin; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; Th, T helper; TYK2, tyrosine kinase 2.
Afonina IS et al. Cell Mol Life Sci. 2021;78:2709-2727. Alwan W, Nestle FO. Clin Exp Rheumatol. 2015;33:S2-S6. Furue M et al. Int J Mol Sci. 020;21:1275. Greb JE et al. Nat Rev Dis Primers. 2016;2:16082. Hawkes JE et al. J Immunol. 2018;201:1605-1613. Nestle FO et al. J Exp Med. 2005;202:135-143. Rendon A, Schäkel K. Int J Mol Sci. 2019;20:1475. Zhang LJ. Front Immunol. 2019;10:1440.
Transduction of extracellular
cytokine signals
Baker KF, Isaacs JD. Ann Rheum Dis. 2018;77:175–187. Morris R et al. Protein Sci. 2018;27:1984–2009.
Certain extracellular signals are particularly relevant to the pathophysiology of PsO: In particular, Type I interferon (IFN), interleukin (IL)-12, IL-23, IL-17, and tumor necrosis factor-α (TNF-α).3,6−9 Type I IFN plays an important role in the initiation of PsO pathology.6,7 IL-23, IL-17 and IL-12 support the development and perpetuation of PsO, while TNF-α affects both the initiation and the perpetuation phases.3,6,8−10 These and other pro-inflammatory cytokines, including IL-6, interferon-gamma (IFN-γ) and IL-22, play an important role in pathogenic signaling and may contribute to the many co-morbidities associated with PsO.3,6,8
Transduction of extracellular
cytokine signals
Baker KF, Isaacs JD. Ann Rheum Dis. 2018;77:175–187. Morris R et al. Protein Sci. 2018;27:1984–2009.
Their functions are listed below:
- Type I IFN is produced by plasmocytic dendritic cells (DCs) in response to anti-microbial peptides and other pro-inflammatory signals from injured or infected keratinocytes.6,12 This signal is received by myeloid and conventional DCs (mDCs, cDCs), stimulating these cells to produce further pro-inflammatory cytokines, such as IL-12 and IL-23.1,13,14
- IL-12 is produced by DCs activated by type I IFN, and stimulates the differentiation of Th1 cells, which produce a number of pro-inflammatory cytokines that activate keratinocytes and support skin lesion development, including IFN-γ and TNF-α.13
- IL-23 is produced by DCs in response to type I IFN or to TNF-α stimulation, and supports the differentiation of Th17 cells.8,13 IL-23−based activation of Th17 cells and the subsequent release of IL-17 family cytokines and other pro-inflammatory cytokines activates keratinocytes and is a known driver of PsO disease.5 This is known as the “IL-23/IL-17 axis of PsO”.8
- IL-17 family cytokines are a key driver of inflammation in PsO.6,8 A study in ex vivo cultured skin showed that IL-17A, IL-17F, IL-17A/F, and IL-17C are expressed at increased levels in PsO and can induce PsO-related inflammation.15
- TNF-α has long been known to be implicated in PsO pathology, although its exact role in PsO pathogenesis has not been completely elucidated yet.8 The current understanding is that TNF-α is implicated in both the initiation and the chronic phase of the disease by indirectly acting to regulate the IL-23/IL-17 inflammatory axis.8,10 TNF-α, in fact, directly stimulates the production of IL-23 by keratinocytes and DCs, as well as potentiates IL-17 signaling by enhancing pro-inflammatory gene expression in keratinocytes.8,10,16
Psoriasis pathophysiology
AMP, anti-microbial peptide; cDC, conventional dendritic cell; IFN, interferon; IL, interleukin; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; Th, T helper; TYK2, tyrosine kinase 2.
Afonina IS et al. Cell Mol Life Sci. 2021;78:2709-2727. Alwan W, Nestle FO. Clin Exp Rheumatol. 2015;33:S2-S6. Furue M et al. Int J Mol Sci. 020;21:1275. Greb JE et al. Nat Rev Dis Primers. 2016;2:16082. Hawkes JE et al. J Immunol. 2018;201:1605-1613. Nestle FO et al. J Exp Med. 2005;202:135-143. Rendon A, Schäkel K. Int J Mol Sci. 2019;20:1475. Zhang LJ. Front Immunol. 2019;10:1440.
- IL-6 is a pro-inflammatory cytokine released by keratinocytes that adds to the inflammatory cascade in PsO.16
- IFN-γ signaling is released by IL-12−differentiated Th1 cells, along with TNF-α, to activate keratinocytes.13
- IL-22 signaling is primarily secreted by Th17 cells, as well as Th22 cells, to activate keratinocyte proliferation in PsO.13,16,17
A certain level of overlap and shared mechanisms in the cytokine signaling pathways is observed in several co-morbidities of PsO.18−24 For instance, the IL-23/IL-17 axis of inflammation is known to be involved in psoriatic arthritis (PsA): In this condition, IL-23 acts directly to increase inflammation in the synovium while also supporting the differentiation of Th17 cells that release IL-17 and TNF-α to activate synoviocytes and differentiate osteoclasts.18,19 At the same time, IL-22 also acts at tendon insertion points to promote pathologic bone formation in enthesitis.19 In cardiovascular disease, IL-17A may contribute to atherosclerotic lesion progression, and cytokines produced by Th17 cells are associated with deep vein thrombosis.20,21 Cytokines such as IL-17, IFN-γ, and TNF-α play a prominent role in the development of the inflammatory processes that accompany inflammatory bowel disease (IBD), metabolic syndrome (MetS), and non-alcoholic fatty liver disease (NAFLD), among others.22−24
Therefore, inflammation is the result of a highly orchestrated chain of extra- and intra-cellular events driven by a broad range of cytokine signals.3,6,8,11−13 Such signaling, and its associated downstream effects, play a crucial role in initiating and maintaining chronic inflammation in PsO as well as other associated co-morbidities.3,6,11,12,18−24
References
- Zhang LJ. Front Immunol. 2019;10:1440.
- Greb JE et al. Nat Rev Dis Primers. 2016;2:16082.
- Korman NJ. Br J Dermatol. 2020;182:840−848.
- Hanada T, Yoshimura A. Cytokine Growth Factor Rev. 2002;13:413−1.
- Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 6th ed. WH Freeman; 2012.
- Hawkes JE et al. J Allergy Clin Immunol. 2017;140:645−653.
- Nestle FO et al. J Exp Med. 2005;202:135−143.
- Afonina IS et al. Cell Mol Life Sci. 2021;78:2709−2727.
- Lee E et al. J Exp Med. 2004;199:125−130.
- Li H et al. Nat Commun. 2018;9:1420.
- Banerjee S et al. Drugs. 2017;77:521−546.
- Chen K et al. J Autoimmun. 2017;83:1−11.
- Alwan W, Nestle FO. Clin Exp Rheumatol. 2015;33:S2−S6.
- Hawkes JE et al. J Immunol. 2018;201:1605−1613.
- Tollenaere MAX et al. Br J Dermatol. 2021;185:585−594.
- Rendon A, Schäkel K. Int J Mol Sci. 2019;20:1475.
- Benham H et al. Arthritis Res Ther. 2013;15:R136.
- Ritchlin CT et al. New Engl J Med. 2017;376:957−970.
- Boutet MA et al. Int J Mol Sci. 2018;19:530.
- Von Stebut E et al. Front Immunol. 2020;10:3096.
- Feng Y et al. Thromb Haemost. 2018;118:1885−1894.
- de Souza HSP, Fiocchi C. Nat Rev Gastroenterol Hepatol. 2016;13:13−27.
- Hao Y et al. Front Immunol. 2021;12:711060.
- Mantovani A et al. Int J Mol Sci. 2016;17:217.