Previously, we demonstrated that intratumoral delivery of adenoviral vector encoding single-chain (sc)IL-23 (Ad.scIL-23) was able to induce systemic antitumor immunity. Here, we examined the role of IL-23 in diabetes in nonobese diabetic mice. Intravenous delivery of Ad.scIL-23 did not accelerate the onset of hyperglycemia but instead resulted in the development of psoriatic arthritis. Ad.scIL-23–treated mice developed erythema, scales, and thickening of the skin, as well as intervertebral disc degeneration and extensive synovial hypertrophy and loss of articular cartilage in the knees. Immunological analysis revealed activation of conventional T helper type 17 cells and IL-17–producing γδ T cells along with a significant depletion and suppression of T cells in the pancreatic lymph nodes. Furthermore, treatment with anti–IL-17 antibody reduced joint and skin psoriatic arthritis pathologies. Thus, these Ad.scIL-23–treated mice represent a physiologically relevant model of psoriatic arthritis for understanding disease progression and for testing therapeutic approaches.—Flores, R. R., Carbo, L., Kim, E., Van Meter, M., De Padilla, C. M. L., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, P. D. Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis–like symptoms in NOD mice. Psoriasis is a chronic inflammatory autoimmune disease of the skin that exists in 3% of the world population. Psoriasis vulgaris, or plaque psoriasis, which manifests as raised itchy erythematous plaques in the skin, is the most common form of psoriasis and accounts for nearly 70% of the patients with psoriasis (1). Psoriatic arthritis (PsA) is the second most common form of psoriasis and is found in ∼30% of patients with psoriasis (1). Patients with PsA have inflammation and autoimmunity occurring in the spine, the peripheral joints, and the site of attachment of ligament to the bone, as well as skin plaques (2). Patients with psoriasis are also prone to develop metabolic disorders, such as type 2 diabetes, cardiovascular disease, and kidney disease. Symptoms of psoriasis in humans include patches of red, inflamed skin with involved areas of the skin developing lesions, referred to as Koebner’s phenomenon. During the early development of psoriatic skin lesions, dermal changes include the formation of twisted dilated vessels along with papillar edema and an infiltrate mainly consisting of dendritic cells and macrophages (3, 4). Within the fully developed lesion, there is extensive thickening of the epidermis (acanthosis) with elongated epidermal rete ridges and dermal papillae with dilated capillaries. The epidermal layer also undergoes extensive hyperplasia, which leads to thickening of stratum corneum (hyperkeratosis), whereas the stratum granulosum decreases. This increase in the number of cells on the surface of the skin leads to thick, silvery scales, another hallmark of the disease. PsA is a chronic arthritic disease, ranging in severity from occasional flare-ups to continuous inflammation that can cause joint damage if not treated. PsA typically affects the large joints, especially those of the lower extremities and distal joints of the fingers. PsA also can affect the spine, leading to degeneration of intervertebral discs and the sacroiliac joints of the pelvis. Epidemiologic data show that in 60% of the cases, psoriatic skin lesions precede joint disease (2). IL-23, a member of the IL-12 cytokine family, is a potent proinflammatory cytokine produced by activated dendritic cells and macrophages. Cytokines in this family exist as heterodimers, and currently there are 4 known members: IL-12, IL-23, IL-27, and IL-35 (5). IL-23 is composed of the IL-12p40 subunit, which it shares with IL-12 and its own subunit, IL-23p19. IL-23 is known to stimulate immune responses and to drive differentiation of CD4+ cells into T helper (Th) type 17 cells. Although the role that IL-12 plays in type 1 diabetes (T1D) has been examined extensively (6–9), the role of IL-23 in diabetes, either directly or indirectly through induction of Th17 cells, is contradictory, depending on the conditions in which Th17 cells are generated. Several studies suggest Th17 cells play a significant role in the etiology of T1D, whereas others suggest Th17 cells are not involved (10–13). However, when Th17 cells do contribute to the etiology of T1D, it appears to rely on cells that can simultaneously produce IL-17 and IFN-γ (13–16). This current study was initially performed to examine whether increasing the expression of IL-23 by adenoviral gene transfer exacerbated or accelerated the establishment and progression of T1D in nonobese diabetic (NOD) mice. Surprisingly, prediabetic NOD mice injected with adenoviral vector encoding single-chain (sc)IL-23 (Ad.scIL-23) didn’t have accelerated onset of hyperglycemia. Instead, the treated mice developed visible symptoms of psoriasis, and histological analysis demonstrated the skin pathology of the classic features of psoriasis. Importantly, mice treated with Ad.scIL-23 also exhibited signs of psoriatic arthritis with evidence of intervertebral disc degeneration and synovial hyperplasia and erosion of the cartilage of the knee. Treatment with an anti–IL-17 antibody clearly implicated IL-17 in driving pathologies associated with psoriatic arthritis in joints, discs, and skin. These results demonstrated that systemic expression of scIL-23 in NOD mice is sufficient to drive not only psoriasis but also psoriatic arthritis. In addition, this novel mouse model of psoriatic arthritis can be used for analysis of disease progression and testing of novel therapeutics.

Flores, R. R., Carbo, L., Kim, E., Van Meter, M., Lopez De Padilla, C. M., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, A. P. D., Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis-like symptoms in NOD mice., <<FASEB JOURNAL>>, 2019; (33): 9505-9515. [doi:10.1096/fj.201900420R] [http://hdl.handle.net/10807/154833]

Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis-like symptoms in NOD mice.

Colangelo, Debora;Pola, Enrico;
2019

Abstract

Previously, we demonstrated that intratumoral delivery of adenoviral vector encoding single-chain (sc)IL-23 (Ad.scIL-23) was able to induce systemic antitumor immunity. Here, we examined the role of IL-23 in diabetes in nonobese diabetic mice. Intravenous delivery of Ad.scIL-23 did not accelerate the onset of hyperglycemia but instead resulted in the development of psoriatic arthritis. Ad.scIL-23–treated mice developed erythema, scales, and thickening of the skin, as well as intervertebral disc degeneration and extensive synovial hypertrophy and loss of articular cartilage in the knees. Immunological analysis revealed activation of conventional T helper type 17 cells and IL-17–producing γδ T cells along with a significant depletion and suppression of T cells in the pancreatic lymph nodes. Furthermore, treatment with anti–IL-17 antibody reduced joint and skin psoriatic arthritis pathologies. Thus, these Ad.scIL-23–treated mice represent a physiologically relevant model of psoriatic arthritis for understanding disease progression and for testing therapeutic approaches.—Flores, R. R., Carbo, L., Kim, E., Van Meter, M., De Padilla, C. M. L., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, P. D. Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis–like symptoms in NOD mice. Psoriasis is a chronic inflammatory autoimmune disease of the skin that exists in 3% of the world population. Psoriasis vulgaris, or plaque psoriasis, which manifests as raised itchy erythematous plaques in the skin, is the most common form of psoriasis and accounts for nearly 70% of the patients with psoriasis (1). Psoriatic arthritis (PsA) is the second most common form of psoriasis and is found in ∼30% of patients with psoriasis (1). Patients with PsA have inflammation and autoimmunity occurring in the spine, the peripheral joints, and the site of attachment of ligament to the bone, as well as skin plaques (2). Patients with psoriasis are also prone to develop metabolic disorders, such as type 2 diabetes, cardiovascular disease, and kidney disease. Symptoms of psoriasis in humans include patches of red, inflamed skin with involved areas of the skin developing lesions, referred to as Koebner’s phenomenon. During the early development of psoriatic skin lesions, dermal changes include the formation of twisted dilated vessels along with papillar edema and an infiltrate mainly consisting of dendritic cells and macrophages (3, 4). Within the fully developed lesion, there is extensive thickening of the epidermis (acanthosis) with elongated epidermal rete ridges and dermal papillae with dilated capillaries. The epidermal layer also undergoes extensive hyperplasia, which leads to thickening of stratum corneum (hyperkeratosis), whereas the stratum granulosum decreases. This increase in the number of cells on the surface of the skin leads to thick, silvery scales, another hallmark of the disease. PsA is a chronic arthritic disease, ranging in severity from occasional flare-ups to continuous inflammation that can cause joint damage if not treated. PsA typically affects the large joints, especially those of the lower extremities and distal joints of the fingers. PsA also can affect the spine, leading to degeneration of intervertebral discs and the sacroiliac joints of the pelvis. Epidemiologic data show that in 60% of the cases, psoriatic skin lesions precede joint disease (2). IL-23, a member of the IL-12 cytokine family, is a potent proinflammatory cytokine produced by activated dendritic cells and macrophages. Cytokines in this family exist as heterodimers, and currently there are 4 known members: IL-12, IL-23, IL-27, and IL-35 (5). IL-23 is composed of the IL-12p40 subunit, which it shares with IL-12 and its own subunit, IL-23p19. IL-23 is known to stimulate immune responses and to drive differentiation of CD4+ cells into T helper (Th) type 17 cells. Although the role that IL-12 plays in type 1 diabetes (T1D) has been examined extensively (6–9), the role of IL-23 in diabetes, either directly or indirectly through induction of Th17 cells, is contradictory, depending on the conditions in which Th17 cells are generated. Several studies suggest Th17 cells play a significant role in the etiology of T1D, whereas others suggest Th17 cells are not involved (10–13). However, when Th17 cells do contribute to the etiology of T1D, it appears to rely on cells that can simultaneously produce IL-17 and IFN-γ (13–16). This current study was initially performed to examine whether increasing the expression of IL-23 by adenoviral gene transfer exacerbated or accelerated the establishment and progression of T1D in nonobese diabetic (NOD) mice. Surprisingly, prediabetic NOD mice injected with adenoviral vector encoding single-chain (sc)IL-23 (Ad.scIL-23) didn’t have accelerated onset of hyperglycemia. Instead, the treated mice developed visible symptoms of psoriasis, and histological analysis demonstrated the skin pathology of the classic features of psoriasis. Importantly, mice treated with Ad.scIL-23 also exhibited signs of psoriatic arthritis with evidence of intervertebral disc degeneration and synovial hyperplasia and erosion of the cartilage of the knee. Treatment with an anti–IL-17 antibody clearly implicated IL-17 in driving pathologies associated with psoriatic arthritis in joints, discs, and skin. These results demonstrated that systemic expression of scIL-23 in NOD mice is sufficient to drive not only psoriasis but also psoriatic arthritis. In addition, this novel mouse model of psoriatic arthritis can be used for analysis of disease progression and testing of novel therapeutics.
2019
Inglese
Flores, R. R., Carbo, L., Kim, E., Van Meter, M., Lopez De Padilla, C. M., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, A. P. D., Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis-like symptoms in NOD mice., <<FASEB JOURNAL>>, 2019; (33): 9505-9515. [doi:10.1096/fj.201900420R] [http://hdl.handle.net/10807/154833]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/154833
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