The data from your phase III randomized trials (ERASURE and FIXTURE) showed that secukinumab at doses of 300 or 150 mg is effective and safe for the treatment of moderate-to-severe psoriasis up to week 52 (Supplementary Table) (77)

The data from your phase III randomized trials (ERASURE and FIXTURE) showed that secukinumab at doses of 300 or 150 mg is effective and safe for the treatment of moderate-to-severe psoriasis up to week 52 (Supplementary Table) (77). pathways, including canonical nuclear factor-B (NF-B), CCAAT/enhancer-binding protein (C/EBP) family, and mitogen-activated protein kinase (MAPK) (Number 1). The key complex, which is consisted of IL-17A/A, IL-17A/F, or IL-17F/F cytokine and IL-17RA or IL-17RC, is the start hallmark of IL-17 signaling transduction (24, 25). Moreover, IL-17RD is also found to be a practical receptor for IL-17A organizations. Together with IL-17RC, IL-17RD acts within the downstream of proinflammatory gene manifestation of IL-17 signaling (12). IL-17R is definitely characterized by a unique structure in its cytoplasmic tail, termed SEF/IL-17R (SEFIR) website (26). IL-17 signaling recruits Take action1 to IL-17R through connection platform of SEFIR website (27). Then Take action1 (also known as an E3 ligase) promotes activation of unique downstream signaling cascades by tumor-necrosis element receptorCassociated element (TRAF) 6 (28). TRAF6 then recruits and stimulates the transforming growth element -triggered kinase 1 and the inhibitor of kappa B kinase complex, resulting in activation of NF-B, C/EBP, C/EBP, and MAPK pathway (29C31). IL-17R-Take action1 complex binds with MEKK3 and MEK5, leading to keratinocyte proliferation (32). Take action1 binds with TRAF2-TRAF5 to keep up the mRNA stability focusing on IL-17 gene (33). In contrast, TRAF3 causes a negative reaction in activation of NF-B and MAPK pathway, resulting in suppressing the formation of IL-17R-Take action1-TRAF6 (34). TRAF6, in combination with A20 (an anti-inflammatory protein) when offered, blocks the activation of NF-B and MAPK to negatively regulate IL-17 signaling (35). Open in a separate window Number 1 IL-23/IL-17 signaling transduction. IL-23 is definitely important in differentiation of Th17 cells, by advertising the production of IL-17A, IL-17F, TNF, and IL-6. IL-23 is definitely heterodimeric and composed of IL-12p40 and IL-23p19. Binding to its receptors, IL-23 entails in phosphorylation of JAKs and TYK, as well as phosphorylation and dimerization of STAT3. Subsequently, STAT3 homodimers regulates the manifestation of ROR-t to promote the gene manifestation. The combination of IL-17A/A, IL-17A/F, or IL-17F/F cytokine with IL-17RA and IL-17RC is found to be a important complex of immune response. IL-17R functions on Take action1 through connection platform of the SEFIR website. Upon ligand binding, Take action1 activates NF-B, C/EBP family, and MAPK pathway by inducing numerous TRAF proteins. Take action1 is essential for mediating ubiquitination of TRAF6, then TRAF6 causes a positive reaction in multiple different pathways. TRAF6 recruits and stimulates the TAK1 and IKK complex, leading to activation of NF-B pathway. IL-17R-Take action1 complex together with TRAF4, MEKK3, and MEK5 to promote activation of ERK5. In addition, ACT1-TRAF2-TRAF5 complex is capable to maintain the mRNA stability targeting the IL-17 gene. The inhibitors A20 and TRAF3 are linked with IL-17RA, dependent on the CBAD. C/EBP, CCAAT/enhancer-binding proteins; NF-B, canonical nuclear factor-B; MAPK, mitogen-activated protein kinase; TRAF, tumor necrosis factor receptor associated factor; TAK1, transforming growth factor- activated kinase 1; IKK, inhibitor of kappa B kinase; ERK5, extracellular signal-regulated kinase 5; RORt, retinoid-related orphan receptor-t; STAT3, signal transducer and activator of transcription 3; JAK2, Janus activated kinase 2; TYK2, tyrosine kinase 2. Psoriasis Role of IL-17 Family Members in Psoriasis In patients with psoriasis, the IL-17 concentrations increase not only in the skin lesions and peripheral blood, but also in the nonlesional and uninvolved skin (36C40). There is evidence indicating that the main sources of IL-17A in patients with psoriasis are the neutrophils (41), Th17 cells Diethylstilbestrol (42), mast cells (43, 44), CD8+ T cells (45), T (46), T cells (47), and innate lymphoid cells (48, 49) in the skin lesions. Psoriasis autoantigens, such as LL37 (50), NFKBIZ (51), ADAMTSL5 (52), and CARMA2 (53), play a crucial role in the production of IL-17A and are involved in the pathogenesis of psoriasis. In psoriasis, the combination of LL37 with the patients own DNA leads to the activation of the Toll-like receptor 9 (54). The self-DNA-LL37 complex acts on Toll-like receptor 7 in the plasmacytoid dendritic cells (DCs) and triggers the activation of the classical myeloid DCs (55) (Physique 2). Subsequently, the myeloid DCs produce IL-12 and IL-23. IL-23 induces the differentiation of the CD4+ T cells into the Th1.The IL-23/IL-17 axis is an important pathway for targeted therapy for inflammatory diseases. (ROR-t) and signal transducer and activator of transcription 3 (STAT3) (21C23). IL-17 induces expression of downstream genes by stimulating activation of pathways, including canonical nuclear factor-B (NF-B), CCAAT/enhancer-binding protein (C/EBP) family, and mitogen-activated protein kinase (MAPK) (Physique 1). The key complex, which is consisted of IL-17A/A, IL-17A/F, or IL-17F/F cytokine and IL-17RA or IL-17RC, is the start hallmark of IL-17 signaling transduction (24, 25). Moreover, IL-17RD is also found to be a functional receptor for IL-17A groups. Together with IL-17RC, IL-17RD acts around the downstream of proinflammatory gene expression of IL-17 signaling (12). IL-17R is usually characterized by a unique structure in its cytoplasmic tail, termed SEF/IL-17R (SEFIR) domain name (26). IL-17 signaling recruits Act1 to IL-17R through conversation platform of SEFIR domain name (27). Then Act1 (also known as an E3 ligase) promotes activation of distinct downstream signaling cascades by tumor-necrosis factor receptorCassociated factor (TRAF) 6 (28). TRAF6 then recruits and stimulates the transforming growth factor -activated kinase 1 and the inhibitor of kappa B kinase complex, resulting in activation of NF-B, C/EBP, C/EBP, and MAPK pathway (29C31). IL-17R-Act1 complex binds with MEKK3 and MEK5, leading to keratinocyte proliferation (32). Act1 binds with TRAF2-TRAF5 to maintain the mRNA stability targeting IL-17 gene (33). In contrast, TRAF3 triggers a negative reaction in activation of NF-B and MAPK pathway, resulting in suppressing the formation of IL-17R-Act1-TRAF6 (34). TRAF6, in combination with A20 (an anti-inflammatory protein) when presented, blocks the activation of NF-B and MAPK to negatively regulate IL-17 signaling (35). Open in a separate window Physique 1 IL-23/IL-17 signaling transduction. IL-23 can be essential in differentiation of Th17 cells, by advertising the creation of IL-17A, IL-17F, TNF, and IL-6. IL-23 can be heterodimeric and made up of IL-12p40 and IL-23p19. Binding to its receptors, IL-23 requires in phosphorylation of JAKs and TYK, aswell as phosphorylation and dimerization of STAT3. Subsequently, STAT3 homodimers regulates the manifestation of ROR-t to market the gene manifestation. The mix of IL-17A/A, IL-17A/F, or IL-17F/F cytokine with IL-17RA and IL-17RC is available to be always a important complicated of immune system response. IL-17R works on Work1 through discussion platform from the SEFIR site. Upon ligand binding, Work1 activates NF-B, C/EBP family members, and MAPK pathway by inducing different TRAF protein. Work1 is vital for mediating ubiquitination of TRAF6, after that TRAF6 triggers an optimistic response in multiple different pathways. TRAF6 recruits and stimulates the TAK1 and IKK complicated, resulting in activation of NF-B pathway. IL-17R-Work1 complicated as well as TRAF4, MEKK3, and MEK5 to market activation of ERK5. Furthermore, ACT1-TRAF2-TRAF5 complicated is competent to keep up with the mRNA balance focusing on the IL-17 gene. The inhibitors A20 and TRAF3 are associated with IL-17RA, reliant on the CBAD. C/EBP, CCAAT/enhancer-binding protein; NF-B, canonical nuclear factor-B; MAPK, mitogen-activated proteins kinase; TRAF, tumor necrosis element receptor associated element; TAK1, transforming development factor- triggered kinase 1; IKK, inhibitor of kappa B kinase; ERK5, extracellular signal-regulated kinase 5; RORt, retinoid-related orphan receptor-t; STAT3, sign transducer and activator of transcription 3; JAK2, Janus triggered kinase 2; TYK2, tyrosine kinase 2. Psoriasis Part of IL-17 FAMILY in Psoriasis In individuals with psoriasis, the IL-17 concentrations boost not merely in your skin lesions and peripheral bloodstream, but also in the nonlesional and uninvolved pores and skin (36C40). There is certainly proof indicating that the primary resources of IL-17A in individuals with psoriasis will be the neutrophils (41), Th17 cells (42), mast cells (43, 44), Compact disc8+ T cells (45), T (46), T cells (47), and innate lymphoid cells (48, 49) in your skin lesions. Psoriasis autoantigens, such as for example LL37 (50), NFKBIZ (51), ADAMTSL5 (52), and CARMA2 (53), play an essential part in the creation of IL-17A and so are mixed up in pathogenesis of psoriasis. In psoriasis, the mix of LL37 using the individuals own DNA qualified prospects towards the activation from the Toll-like receptor 9 (54). The self-DNA-LL37 complicated functions on Toll-like receptor 7 in the plasmacytoid dendritic cells (DCs) and causes the activation from the traditional myeloid DCs (55) (Shape 2). Subsequently, the myeloid DCs make IL-12 and IL-23. IL-23 induces the differentiation from the Compact disc4+ T cells in to the Th1 cells and Th17 cells by.In the landmark UltIMMa-2 and UltIMMa-1 research, 150 mg risankizumab demonstrated beneficial in the treating moderate-to-severe psoriasis weighed against a placebo and ustekinumab (Supplementary Desk) (118). Tildrakizumab is a humanized IgG1 monoclonal antagonist, targeting IL-23p19. summarize the most recent understanding of the biology, signaling, and pathophysiological features from the IL-23/IL-17 axis in inflammatory pores and skin diseases. The available biologics targeting the axis can be discussed presently. activating the transcription element retinoid-related orphan receptor-t (ROR-t) and sign transducer and activator of transcription 3 (STAT3) (21C23). IL-17 induces manifestation of downstream genes by stimulating activation of pathways, including canonical nuclear factor-B (NF-B), CCAAT/enhancer-binding proteins (C/EBP) family members, and mitogen-activated proteins kinase (MAPK) (Shape 1). The main element complicated, which is contains IL-17A/A, IL-17A/F, or IL-17F/F cytokine and IL-17RA or IL-17RC, may be the begin hallmark of IL-17 signaling transduction (24, 25). Furthermore, IL-17RD can be found to be always a practical receptor for IL-17A organizations. As well as IL-17RC, IL-17RD works for the downstream of proinflammatory gene manifestation of IL-17 signaling (12). IL-17R can be characterized by a Diethylstilbestrol distinctive framework in its cytoplasmic tail, termed SEF/IL-17R (SEFIR) site (26). IL-17 signaling recruits Work1 to IL-17R through discussion system of SEFIR site (27). Then Work1 (also called an E3 ligase) promotes activation of specific downstream signaling cascades by tumor-necrosis element receptorCassociated element (TRAF) 6 (28). TRAF6 after that recruits and stimulates the changing growth element -triggered kinase 1 as well as the inhibitor of kappa B kinase complicated, leading to activation of NF-B, C/EBP, C/EBP, and MAPK pathway (29C31). IL-17R-Work1 complicated binds with MEKK3 and MEK5, resulting in keratinocyte proliferation (32). Work1 binds with TRAF2-TRAF5 to keep up the mRNA balance focusing on IL-17 gene (33). On the other hand, TRAF3 triggers a poor response in activation of NF-B and MAPK pathway, leading to suppressing the forming of IL-17R-Work1-TRAF6 (34). TRAF6, in conjunction with A20 (an anti-inflammatory proteins) when shown, blocks the activation of NF-B and MAPK to adversely regulate IL-17 signaling (35). Open up in another window Shape 1 IL-23/IL-17 signaling transduction. IL-23 can be essential in differentiation of Th17 cells, by advertising the creation of IL-17A, IL-17F, TNF, and IL-6. IL-23 can be heterodimeric and made up of IL-12p40 and IL-23p19. Binding to its receptors, IL-23 requires in phosphorylation of JAKs and TYK, aswell as phosphorylation and dimerization of STAT3. Subsequently, STAT3 homodimers regulates the manifestation of ROR-t to market the gene manifestation. The mix of IL-17A/A, IL-17A/F, or IL-17F/F cytokine with IL-17RA and IL-17RC is available to be always a essential complicated of immune system response. IL-17R serves on Action1 through connections platform DP1 from the SEFIR domains. Upon ligand binding, Action1 activates NF-B, C/EBP family members, and MAPK pathway by inducing several TRAF protein. Action1 is vital for mediating ubiquitination of TRAF6, after that TRAF6 triggers an optimistic response in multiple different pathways. TRAF6 recruits and stimulates the TAK1 and IKK complicated, resulting in activation of NF-B pathway. IL-17R-Action1 complicated as well as TRAF4, MEKK3, and MEK5 to market activation of ERK5. Furthermore, ACT1-TRAF2-TRAF5 complicated is competent to keep up with the mRNA balance concentrating on the IL-17 gene. The inhibitors A20 and TRAF3 are associated with IL-17RA, reliant on the CBAD. C/EBP, CCAAT/enhancer-binding protein; NF-B, canonical nuclear factor-B; MAPK, mitogen-activated proteins kinase; TRAF, tumor necrosis aspect receptor associated aspect; TAK1, transforming development factor- turned on kinase 1; IKK, inhibitor of kappa B kinase; ERK5, extracellular signal-regulated kinase 5; RORt, retinoid-related orphan receptor-t; STAT3, indication transducer and activator of transcription 3; JAK2, Janus turned on kinase 2; TYK2, tyrosine kinase 2. Psoriasis Function of IL-17 FAMILY in Psoriasis In sufferers with psoriasis, the IL-17 concentrations boost not merely in your skin lesions and peripheral bloodstream, but also in the nonlesional and uninvolved epidermis (36C40). There is certainly proof indicating that the primary resources of IL-17A in sufferers with psoriasis will be the neutrophils (41), Th17 cells (42), mast cells (43, 44), Compact disc8+ T cells (45), T (46), T cells (47), and innate lymphoid cells (48, 49) in your skin lesions. Psoriasis autoantigens, such as for example LL37 (50), NFKBIZ (51), ADAMTSL5 (52), and CARMA2 (53), play an essential function in the creation of IL-17A and so are mixed up in pathogenesis of psoriasis. In psoriasis, the mix of LL37 using the sufferers very own DNA.An open-label research indicates that, at week 40, a moderate-to-marked improvement from the modified Sartorius rating was achieved in 82% (14/17) of sufferers with HS receiving IL-12/23 biologic ustekinumab therapy (134). with psoriasis, atopic dermatitis, hidradenitis suppurativa, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Right here, we summarize the most recent understanding of the biology, signaling, and pathophysiological features from the IL-23/IL-17 axis in inflammatory epidermis diseases. The available biologics concentrating on the axis can be talked about. activating the transcription aspect retinoid-related orphan receptor-t (ROR-t) and indication transducer and activator of transcription 3 (STAT3) (21C23). IL-17 induces appearance of downstream genes by stimulating activation of pathways, including canonical nuclear factor-B (NF-B), CCAAT/enhancer-binding proteins (C/EBP) family members, and mitogen-activated proteins kinase (MAPK) (Amount 1). The main element complicated, which is contains IL-17A/A, IL-17A/F, or IL-17F/F cytokine and IL-17RA or IL-17RC, may be the begin hallmark of IL-17 signaling transduction (24, 25). Furthermore, IL-17RD can be found to be always a useful receptor for IL-17A groupings. As well as IL-17RC, IL-17RD serves over the downstream of proinflammatory gene appearance of IL-17 signaling (12). IL-17R is normally characterized by a distinctive framework in its cytoplasmic tail, termed SEF/IL-17R (SEFIR) domains (26). IL-17 signaling recruits Action1 to IL-17R through connections system of SEFIR domains (27). Then Action1 (also called an E3 ligase) promotes activation of distinctive downstream signaling cascades by tumor-necrosis aspect receptorCassociated aspect (TRAF) 6 (28). TRAF6 after that recruits and stimulates the changing growth aspect -turned on kinase 1 as well as the inhibitor of kappa B kinase complicated, leading to activation of NF-B, C/EBP, C/EBP, and MAPK pathway (29C31). IL-17R-Action1 complicated binds with MEKK3 and MEK5, resulting in keratinocyte proliferation (32). Action1 binds with TRAF2-TRAF5 to keep the mRNA balance concentrating on IL-17 gene (33). On the other hand, TRAF3 triggers a poor response in activation of NF-B and MAPK pathway, leading to suppressing the forming of IL-17R-Action1-TRAF6 (34). TRAF6, in conjunction with A20 (an anti-inflammatory proteins) when provided, blocks the activation of NF-B and MAPK to adversely regulate IL-17 signaling (35). Open up in another window Body 1 IL-23/IL-17 signaling transduction. IL-23 is certainly essential in differentiation of Th17 cells, by marketing the creation of IL-17A, IL-17F, TNF, and IL-6. IL-23 is certainly heterodimeric and made up of IL-12p40 and IL-23p19. Binding to its receptors, IL-23 consists of in phosphorylation Diethylstilbestrol of JAKs and TYK, aswell as phosphorylation and dimerization of STAT3. Subsequently, STAT3 homodimers regulates the appearance of ROR-t to market the gene appearance. The mix of IL-17A/A, IL-17A/F, or IL-17F/F cytokine with IL-17RA and IL-17RC is available to be always a essential complicated of immune system response. IL-17R serves on Action1 through relationship platform from the SEFIR area. Upon ligand binding, Action1 activates NF-B, C/EBP family members, and MAPK pathway by inducing several TRAF protein. Action1 is vital for mediating ubiquitination of TRAF6, after that TRAF6 triggers an optimistic response in multiple different pathways. TRAF6 recruits and stimulates the TAK1 and IKK complicated, resulting in activation of NF-B pathway. IL-17R-Action1 complicated as well as TRAF4, MEKK3, and MEK5 to market activation of ERK5. Furthermore, ACT1-TRAF2-TRAF5 complicated is competent to keep up with the mRNA balance concentrating on the IL-17 gene. The inhibitors A20 and TRAF3 are associated with IL-17RA, reliant on the CBAD. C/EBP, CCAAT/enhancer-binding protein; NF-B, canonical nuclear factor-B; MAPK, mitogen-activated proteins kinase; TRAF, tumor necrosis aspect receptor associated aspect; TAK1, transforming development factor- turned on kinase 1; IKK, inhibitor of kappa B kinase; ERK5, extracellular signal-regulated kinase 5; RORt, retinoid-related orphan receptor-t; STAT3, indication transducer and activator of transcription 3; JAK2, Janus turned on kinase 2; TYK2, tyrosine kinase 2. Psoriasis Function of IL-17 FAMILY in Psoriasis In sufferers with psoriasis, the IL-17 concentrations boost not merely in your skin lesions and peripheral bloodstream, but also in the nonlesional and uninvolved epidermis (36C40). There is certainly proof indicating that the primary resources of IL-17A in sufferers with psoriasis will be the neutrophils (41), Th17 cells (42), mast cells (43, 44), Compact disc8+ T cells (45), T (46), T.Metabolic disorders, such as for example hyperglycemia (68) and cardiovascular risks (69), are connected with psoriasis also. From IL-17A Apart, the various other IL-17 family (IL-17C, E, and F) can also be mixed up in pathogenesis of psoriasis (70C72). biology, signaling, and pathophysiological features from the IL-23/IL-17 axis in inflammatory epidermis diseases. The available biologics concentrating on the axis can be talked about. activating the transcription aspect retinoid-related orphan receptor-t (ROR-t) and indication transducer and activator of transcription 3 (STAT3) (21C23). IL-17 induces appearance of downstream genes by stimulating activation of pathways, including canonical nuclear factor-B (NF-B), CCAAT/enhancer-binding proteins (C/EBP) family members, and mitogen-activated proteins kinase (MAPK) (Body 1). The main element complicated, which is contains IL-17A/A, IL-17A/F, or IL-17F/F cytokine and IL-17RA or IL-17RC, may be the begin hallmark of IL-17 signaling transduction (24, 25). Furthermore, IL-17RD can be found to be always a useful receptor for IL-17A groupings. As well as IL-17RC, IL-17RD serves in the downstream of proinflammatory gene appearance of IL-17 signaling (12). IL-17R is certainly characterized by a distinctive framework in its cytoplasmic tail, termed SEF/IL-17R (SEFIR) area (26). IL-17 signaling recruits Action1 to IL-17R through relationship system of SEFIR area (27). Then Action1 (also called an E3 ligase) promotes activation of distinctive downstream signaling cascades by tumor-necrosis aspect receptorCassociated aspect (TRAF) 6 (28). TRAF6 after that recruits and stimulates the changing growth aspect -turned on kinase 1 as well as the inhibitor of kappa B kinase complicated, leading to activation of NF-B, C/EBP, C/EBP, and MAPK pathway (29C31). IL-17R-Action1 complicated binds with MEKK3 and MEK5, resulting in keratinocyte proliferation (32). Action1 binds with TRAF2-TRAF5 to keep the mRNA balance targeting IL-17 gene (33). In contrast, TRAF3 triggers a negative reaction in activation of NF-B and MAPK pathway, resulting in suppressing the formation of IL-17R-Act1-TRAF6 (34). TRAF6, in combination with A20 (an anti-inflammatory protein) when presented, blocks the activation of NF-B and MAPK to negatively regulate IL-17 signaling (35). Open in a separate window Figure 1 IL-23/IL-17 signaling transduction. IL-23 is important in differentiation of Th17 cells, by promoting the production of IL-17A, IL-17F, TNF, and IL-6. IL-23 is heterodimeric and composed of IL-12p40 and IL-23p19. Binding to its receptors, IL-23 involves in phosphorylation of JAKs and TYK, as well as phosphorylation and dimerization of STAT3. Subsequently, STAT3 homodimers regulates the expression of ROR-t to promote the gene expression. The combination of IL-17A/A, IL-17A/F, or IL-17F/F cytokine with IL-17RA and IL-17RC is found to be a crucial complex of immune response. IL-17R acts on Act1 through interaction platform of the SEFIR domain. Upon ligand binding, Act1 activates NF-B, C/EBP family, and MAPK pathway by inducing various TRAF proteins. Act1 is essential for mediating ubiquitination of TRAF6, then TRAF6 triggers a positive reaction in multiple different pathways. TRAF6 recruits and stimulates the TAK1 and IKK complex, leading to activation of NF-B pathway. IL-17R-Act1 complex together with TRAF4, MEKK3, and MEK5 to promote activation of ERK5. In addition, ACT1-TRAF2-TRAF5 complex is capable to maintain the mRNA stability targeting the IL-17 gene. The inhibitors A20 and TRAF3 are linked with IL-17RA, dependent on the CBAD. C/EBP, CCAAT/enhancer-binding proteins; NF-B, canonical nuclear factor-B; MAPK, mitogen-activated protein kinase; TRAF, tumor necrosis factor receptor associated factor; TAK1, transforming growth factor- activated kinase 1; IKK, inhibitor of kappa B kinase; ERK5, extracellular signal-regulated kinase 5; RORt, retinoid-related orphan receptor-t; STAT3, signal transducer and activator of transcription 3; JAK2, Janus activated kinase 2; TYK2, tyrosine kinase 2. Psoriasis Role of IL-17 Family Members in Psoriasis In patients with psoriasis, the IL-17 concentrations increase not only in the skin lesions and peripheral blood, but also in the nonlesional and uninvolved skin (36C40). There is evidence indicating that the main sources of IL-17A in patients with psoriasis are the neutrophils (41), Th17 cells (42), mast cells (43, 44), CD8+ T cells (45), T (46), T cells (47), and innate lymphoid cells (48, 49) in the skin lesions. Psoriasis autoantigens, such as LL37 (50), NFKBIZ (51), ADAMTSL5 (52), and CARMA2 (53), play a crucial role in the production of IL-17A and are involved in the pathogenesis of psoriasis. In psoriasis, the combination of LL37 with the patients own DNA leads to the activation of the Toll-like receptor 9 (54). The self-DNA-LL37 complex acts on Toll-like receptor 7 in the plasmacytoid dendritic cells (DCs) and triggers the activation of the classical myeloid DCs (55) (Figure 2). Subsequently, the myeloid DCs produce IL-12 and IL-23. IL-23 induces the differentiation of the CD4+ T cells into the Th1 cells and Th17 cells by stimulating the transcription factor ROR-t and STAT3 (56, 57). Thereafter, the activated Th17 cells secrete Th17 cytokines (IL-17A, IL-22, and TNF-),.