Etanercept Downregulates the Th17 Pathway and Decreases the IL-17+/IL-10+ Cell Ratio in Patients with Psoriasis Vulgaris

Antiga, Emiliano; Volpi, Walter; Cardilicchia, Elisa; Maggi, Laura; Filì, Lucia; Manuelli, Cinzia; Parronchi, Paola; Fabbri, Paolo; Caproni, Marzia

doi:10.1007/s10875-012-9716-x

Cited by 27 publications

(20 citation statements)

References 39 publications

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“…In another remitting patient LL37-specific T cells lost IL-17-secretion capacity. Noteworthy, the two improving patients received Etanercept, a TNF-a blocker reported to inhibit IL-17 and increase IL-10 production by T cells 46,47 . Emergence of IL-10 plus vanishing of IFN-g/Th17 responses in patients that lowered PASI is consistent with the correlation that we found between presence of LL37-specific T cells producing IFN-g, IL-17, IL-21, IL-22 (refs 7-9), (but not Tregs/Th2-cytokines IL-10/IL-4) with moderateto-severe psoriasis.…”

Section: Discussionmentioning

confidence: 99%

The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis

et al. 2014

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Psoriasis is a common T-cell-mediated skin disease with 2-3% prevalence worldwide. Psoriasis is considered to be an autoimmune disease, but the precise nature of the autoantigens triggering T-cell activation remains poorly understood. Here we find that two-thirds of patients with moderate-to-severe plaque psoriasis harbour CD4 þ and/or CD8 þ T cells specific for LL37, an antimicrobial peptide (AMP) overexpressed in psoriatic skin and reported to trigger activation of innate immune cells. LL37-specific T cells produce IFN-g, and CD4 þ T cells also produce Th17 cytokines. LL37-specific T cells can infiltrate lesional skin and may be tracked in patients blood by tetramers staining. Presence of circulating LL37-specific T cells correlates significantly with disease activity, suggesting a contribution to disease pathogenesis. Thus, we uncover a role of LL37 as a T-cell autoantigen in psoriasis and provide evidence for a role of AMPs in both innate and adaptive immune cell activation.

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Section: Discussionmentioning

confidence: 99%

The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis

et al. 2014

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“…The ability of TNFα to promote pulmonary IL-17A expression after O 3 exposure is consistent with the role of TNFα in other pathogenic states. For example, etanercept reduces the elevated blood and skin Th17 cells observed in patients with psoriasis [26]. Similarly, another anti-TNFα therapy, infliximab, reduces IL-17A in ocular fluid from uveitis patients with Behcet’s disease [27].…”

Section: Discussionmentioning

confidence: 99%

“…Instead, TNFα recruits neutrophils in part by inducing expression of other cytokines and chemokines [24], [25]. In several pathological states, TNFα induces the expression of IL-17A [26], [27]. Hence, we hypothesized that TNFα contributes to neutrophil recruitment following subacute O 3 exposure by promoting recruitment to or activation of IL-17A + γδ T cells in the lungs.…”

Section: Introductionmentioning

confidence: 99%

γδ T Cells Are Required for Pulmonary IL-17A Expression after Ozone Exposure in Mice: Role of TNFα

Mathews¹,

Williams²,

Brand³

et al. 2014

PLoS ONE

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Ozone is an air pollutant that causes pulmonary symptoms. In mice, ozone exposure causes pulmonary injury and increases bronchoalveolar lavage macrophages and neutrophils. We have shown that IL-17A is important in the recruitment of neutrophils after subacute ozone exposure (0.3 ppm for 24–72 h). We hypothesized that γδ T cells are the main producers of IL-17A after subacute ozone. To explore this hypothesis we exposed wildtype mice and mice deficient in γδ T cells (TCRδ−/−) to ozone or room air. Ozone-induced increases in BAL macrophages and neutrophils were attenuated in TCRδ−/− mice. Ozone increased the number of γδ T cells in the lungs and increased pulmonary Il17a mRNA expression and the number of IL-17A+ CD45+ cells in the lungs and these effects were abolished in TCRδ−/− mice. Ozone-induced increases in factors downstream of IL-17A signaling, including G-CSF, IL-6, IP-10 and KC were also decreased in TCRδ−/− versus wildtype mice. Neutralization of IL-17A during ozone exposure in wildtype mice mimicked the effects of γδ T cell deficiency. TNFR2 deficiency and etanercept, a TNFα antagonist, also reduced ozone-induced increases in Il17a mRNA, IL-17A+ CD45+ cells and BAL G-CSF as well as BAL neutrophils. TNFR2 deficient mice also had decreased ozone-induced increases in Ccl20, a chemoattractant for IL-17A+ γδ T cells. Il17a mRNA and IL-17A+ γδ T cells were also lower in obese Cpefat versus lean WT mice exposed to subacute ozone, consistent with the reduced neutrophil recruitment observed in the obese mice. Taken together, our data indicate that pulmonary inflammation induced by subacute ozone requires γδ T cells and TNFα-dependent recruitment of IL-17A+ γδ T cells to the lung.

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“…The use of etanercept, a competitive inhibitor of TNF‐α, for the treatment of HS was less encouraging and showed only minimal and inconsistent efficacy . However, in patients with psoriasis, etanercept downregulated the Th17 pathway and improved psoriasis‐associated depression …”

Section: Therapeutic Agents Affect the T Helper 17 Cell/regulatory T‐mentioning

confidence: 99%

T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities

et al. 2018

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Etanercept Downregulates the Th17 Pathway and Decreases the IL-17+/IL-10+ Cell Ratio in Patients with Psoriasis Vulgaris

Abstract: Our results confirmed the role of Th17 cells in the pathogenesis of psoriasis. Etanercept, but not acitretin, was able to downregulate the Th17 pathway and to increase the percentages of IL-10-producing cells in the skin.

Cited by 27 publications

References 39 publications

The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis

The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis

γδ T Cells Are Required for Pulmonary IL-17A Expression after Ozone Exposure in Mice: Role of TNFα

T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities

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