IL‐17A expressed on neutrophil extracellular traps promotes mesenchymal stem cell differentiation toward bone‐forming cells in ankylosing spondylitis

Papagoras, Charalampos; Chrysanthopoulou, Akrivi; Mitsios, Alexandros; Ntinopoulou, Maria; Tsironidou, Victoria; Batsali, Aristea; Papadaki, Helen Α.; Skendros, Panagiotis; Ritis, Konstantinos

doi:10.1002/eji.202048878

Cited by 44 publications

(38 citation statements)

References 70 publications

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“…We have recently demonstrated the involvement of NETs and NET-associated cytokines in UVB-induced skin inflammation [9], and others also demonstrated association of IL-17 with neutrophil NETs [76] or extracellular traps released by TH17 cells [57]. In the current study, we found PAF-induced expression of IL-17A, TNFα, IFNγ, and IFNα in neutrophils, and these cytokines can be released to the extracellular space with NETs during NETosis.…”

Section: Discussionsupporting

confidence: 71%

Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation

Lyu

Liao

et al. 2021

Preprint

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Objective. Ultraviolet B (UVB) is an important trigger of skin inflammation and lupus with recruitment of leukocytes to inflamed skin. Neutrophil NETosis has been implicated in pathogenesis of lupus erythematosus. We recently reported that nuclear envelope rupture and NET formation is driven by PKCα-mediated nuclear lamin B disassembly, with involvement of NETosis in UVB-induced skin inflammation. Studies have shown that cytoskeletal networks are involved in NETosis. However, it is still unknown how cytoskeletal networks and their upstream ROCK are involved in NET formation as well as UVB-induced skin inflammation. Methods. The involvements of actomyosin cytoskeletal networks and ROCK1 in NETosis were studied in vitro. Mice with hematopoietic specific ROCK1 deficiency were irradiated by UVB to investigate NET formation in vivo and its involvement in skin inflammation. Results. In time course studies, PKCα nuclear translocation was very well matched with actin polymerization and ROCK1 activation. Inhibition of actin polymerization or ROCK/MLCK/myosin pathway with chemical inhibitors decreased nuclear translocation of PKCα and NETosis in vitro. Furthermore, genetic deficiency of ROCK1 inhibited NET formation ex vivo. Hematopoietic specific ROCK1 deficiency ameliorated UVB-induced skin inflammation in mice with reduced skin thickness by attenuating NET formation and the extracellular display of NET-associated IL-17A, TNFα, IFNγ, and IFNα in the inflamed skin. Conclusion. ROCK1 regulated neutrophils for NET formation by modulation of PKCα nuclear translocation through actomyosin cytoskeletal networks. ROCK1 deficiency ameliorates UVB-induced skin inflammation by inhibition of NETosis and display of NET-associated cytokines. This study provides insights into novel therapeutics on NETosis-related diseases.

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Section: Discussionsupporting

confidence: 71%

Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation

Lyu

Liao

et al. 2021

Preprint

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“…We have recently demonstrated the involvement of NETs and NET-associated cytokines in UVB-induced skin inflammation 9 , and others also demonstrated the association of IL-17 with neutrophil NETs 77 or extracellular traps released by TH17 cells 58 . In the current study, we found PAF-induced expression of IL-17A, TNFα, IFNγ, and IFNα in neutrophils, and these cytokines can be released with NETs to the extracellular space during NETosis.…”

Section: Discussionmentioning

confidence: 93%

Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation

Lyu

Liao

et al. 2022

Theranostics

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Objective: Ultraviolet B (UVB) is an important trigger of skin inflammation and lupus with leukocyte recruitment to inflamed skin. We recently reported the involvement of neutrophil NETosis in UVB-induced skin inflammation, and that NETotic nuclear envelope rupture is driven by PKCα-mediated nuclear lamin B disassembly. To address the role of Actin cytoskeleton in NETosis, we investigated the effects of Rho kinase (ROCK) and its downstream actomyosin cytoskeletal networks on PKCα nuclear translocation and NET formation, as well as their involvement in UVB-induced skin inflammation. Methods: We studied the dynamic changes of ROCK and actomyosin cytoskeletal networks during NETosis induction and their involvement in PKCα nuclear translocation. Using mice with hematopoietic-specific ROCK1 deficiency, we investigated the effects of ROCK1 deficiency on NETosis, and its involvement in UVB-induced skin inflammation. Results: Our time course studies demonstrated the dynamic changes of actin polymerization and ROCK activation, support the role of actin cytoskeleton in nuclear translocation of cytosolic PKCα in early stage of NETosis induction. Inhibition of actin polymerization or key molecules of the ROCK/MLCK/myosin pathway decreased PKCα nuclear translocation and NET formation. Genetic deficiency of ROCK1, inhibited NETosis ex vivo and in vivo , decreased extracellular display of NET-associated IL-17A, TNFα, IFNγ, and IFNα in inflamed skin, which were correlated with the ameliorated skin inflammation in UVB-irradiated mice with hematopoietic-specific ROCK1 deficiency. Conclusions: ROCK regulated NETosis through modulation of PKCα nuclear translocation via actomyosin cytoskeletal networks in neutrophils. ROCK1 deficiency ameliorated UVB-induced skin inflammation by attenuation of NETosis and NET-associated cytokines.

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“…In the present study, we found for the rst time that IL-17A has a role in enhancing osteogenic differentiation of LFCs. Numerous evidence has previously shown that IL-17A can promote bone formation [19,[36][37][38]]. However, some other studies have concluded the opposite [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…Several pieces of experimental evidence indicate that IL-17A plays an signi cant role in promoting heterotopic ossi cation [18]. In addition, IL-17 could promote osteogenic differentiation of human mesenchymal stem cells [19]. However, its effect on osteogenic differentiation of ligamentum avum cells (LFCs) remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-17A promotes proliferation and osteogenic differentiation of human ligamentum flavum cells through regulation of β-catenin nuclear translocation

Lin

Jiang

Xiang

et al. 2022

Preprint

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Thoracic ossification of the ligamentum flavum (TOLF) is the leading cause of thoracic spinal stenosis with no specifc treatment available. IL-17A has received widespread attention for its key contribution in the regulation of bone metabolism and heterotopic ossification. However, it is unclear whether IL-17A is involved in TOLF. Our results showed that IL-17A expression was elevated in ossified ligamentum flavum tissue compared to normal ligamentum flavum. In in vitro experiments, IL-17A stimulation promoted the proliferation and osteogenic differentiation of ligamentum flavum cells (LFCs) derived from TOLF patients. Mechanistically, we found that IL-17A stimulation promoted nuclear translocation of β-catenin, whereas silencing of β-catenin attenuated IL-17A-induced proliferation and osteogenic differentiation of LFCs. Furthermore, co-culture of T helper 17 (Th17) cells with LFCs showed that IL-17A secreted by Th17 cells significantly enhanced the accumulation of β-catenin in the nucleus, as well as the proliferation and osteogenic differentiation of LFCs. However, these effects were markedly attenuated after the neutralization of IL-17A. Our study demonstrates that IL-17A secreted by Th17 cells in the lesion microenvironment may be involved in TOLF by regulating nuclear translocation of β-catenin to promote proliferation and osteogenic differentiation of LFCs. This study helps to elucidate the pathological mechanism of TOLF and suggests the possibility of IL-17A as a potential target for the prevention and treatment of TOLF.

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IL‐17A expressed on neutrophil extracellular traps promotes mesenchymal stem cell differentiation toward bone‐forming cells in ankylosing spondylitis

Cited by 44 publications

References 70 publications

Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation

Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation

Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation

Interleukin-17A promotes proliferation and osteogenic differentiation of human ligamentum flavum cells through regulation of β-catenin nuclear translocation

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