insight - Immunology - # Role of Semaphorin 4A in the Pathogenesis of Psoriasis

Downregulation of Semaphorin 4A in Keratinocytes Reflects the Features of Non-Lesional Psoriasis

Q: What other signaling pathways or mechanisms, besides mTOR, might be involved in the regulation of keratinocyte differentiation and T17 cell infiltration in the context of Sema4A downregulation?

In addition to the mTOR pathway, several other signaling pathways and mechanisms could be implicated in the regulation of keratinocyte differentiation and T17 cell infiltration in the context of Sema4A downregulation. One key pathway is the NF-κB pathway, which is known to play a crucial role in the pathogenesis of psoriasis. NF-κB activation in keratinocytes leads to the production of pro-inflammatory cytokines and chemokines, contributing to the recruitment and activation of immune cells, including T17 cells. Downregulation of Sema4A could potentially dysregulate NF-κB signaling, exacerbating the inflammatory response in the skin. Moreover, the JAK-STAT pathway is another important signaling cascade involved in immune responses and skin homeostasis. Dysregulation of JAK-STAT signaling in keratinocytes can lead to altered cytokine production and immune cell recruitment, further promoting the development of psoriatic features. Sema4A downregulation may impact the JAK-STAT pathway, influencing the differentiation of T17 cells and keratinocyte function. Additionally, the Wnt/β-catenin pathway is essential for skin development and regeneration. Aberrant activation of this pathway can disrupt keratinocyte differentiation and barrier function, contributing to skin disorders like psoriasis. Sema4A downregulation may interact with the Wnt/β-catenin pathway, affecting epidermal homeostasis and immune cell infiltration in psoriatic skin.

Q: What other skin or organ-specific functions of Sema4A could be explored to understand its broader implications in health and disease?

Beyond its role in psoriasis and immune regulation, Sema4A has diverse functions in various tissues and organs that warrant exploration to understand its broader implications in health and disease. In the context of skin biology, Sema4A may play a role in wound healing and tissue repair by modulating cell migration, proliferation, and angiogenesis. Understanding how Sema4A influences these processes could provide insights into skin regeneration and scar formation. Moreover, Sema4A has been implicated in neurological disorders, where it acts as a guidance cue for axon guidance and neuronal development. Investigating the role of Sema4A in neurodevelopmental disorders, such as autism and schizophrenia, could uncover its impact on brain function and connectivity. In the context of cancer, Sema4A has been associated with tumor progression and metastasis in various malignancies. Exploring the interactions between Sema4A and tumor microenvironment components could reveal its potential as a therapeutic target for cancer treatment. Furthermore, Sema4A may have implications in cardiovascular health, as it has been linked to vascular development and endothelial cell function. Investigating the role of Sema4A in cardiovascular diseases, such as atherosclerosis and hypertension, could provide insights into its impact on vascular homeostasis and disease pathogenesis. Overall, exploring the diverse functions of Sema4A in different tissues and organs can shed light on its multifaceted roles in health and disease, offering potential therapeutic avenues for a wide range of conditions beyond psoriasis.

Q: How might the upregulation of Sema4A on immune cells, such as lymphocytes and monocytes, contribute to the pathogenesis of psoriasis, and could this be a potential therapeutic target?

The upregulation of Sema4A on immune cells, particularly lymphocytes and monocytes, can contribute to the pathogenesis of psoriasis by promoting pro-inflammatory responses and immune cell activation. Sema4A signaling in T cells has been shown to enhance Th17 differentiation and cytokine production, leading to the amplification of the inflammatory cascade in psoriatic lesions. Additionally, Sema4A expression on monocytes can modulate their activation and cytokine secretion, further fueling the inflammatory milieu in the skin. Targeting the upregulated Sema4A signaling on immune cells could represent a promising therapeutic strategy for psoriasis. By inhibiting Sema4A-mediated pathways in lymphocytes and monocytes, it may be possible to dampen the exaggerated immune response and reduce the production of pro-inflammatory cytokines involved in psoriatic inflammation. This approach could help mitigate disease severity, reduce skin lesions, and improve patient outcomes. Furthermore, blocking Sema4A signaling on immune cells could potentially modulate the immune microenvironment in psoriatic skin, leading to a more balanced immune response and decreased tissue damage. By targeting Sema4A as a therapeutic intervention, it may be possible to achieve better disease management and potentially prevent disease progression in individuals with psoriasis. Further research into the specific mechanisms of Sema4A action on immune cells is warranted to develop targeted therapies that can effectively modulate the immune dysregulation seen in psoriasis.

Conceitos Básicos

Downregulation of Semaphorin 4A in keratinocytes plays a crucial role in the development of psoriatic non-lesional features, including epidermal thickening and increased T17 cell infiltration, potentially through the upregulation of mTOR signaling.

Resumo

The study investigated the role of Semaphorin 4A (Sema4A) in the pathogenesis of psoriasis. Key findings:

Sema4A expression was downregulated in the keratinocytes of both psoriatic lesions and non-lesions compared to controls, while it was upregulated in blood lymphocytes and monocytes of psoriasis patients.
Sema4A knockout (KO) mice exhibited more severe imiquimod-induced dermatitis compared to wild-type (WT) mice, with increased T17 cell infiltration and epidermal thickening, characteristic of psoriatic non-lesions.
Bone marrow chimeric experiments suggested that the absence of Sema4A in non-hematopoietic cells, likely keratinocytes, was primarily responsible for the exacerbated imiquimod-induced dermatitis in Sema4AKO mice.
The epidermis of Sema4AKO mice and human psoriatic non-lesions showed upregulation of mTOR complex 1 signaling. Inhibition of mTOR signaling modulated the expression of keratinocyte differentiation markers in Sema4AKO mice.
These findings indicate that the downregulation of Sema4A in keratinocytes plays a crucial role in the development of psoriatic non-lesional features, potentially through the upregulation of mTOR signaling. Targeting the Sema4A-mTOR axis could be a promising strategy for psoriasis treatment and prevention.

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biorxiv.org

Estatísticas

Sema4A expression was significantly downregulated in the keratinocytes of psoriatic lesions and non-lesions compared to controls.
Imiquimod-induced ear swelling on day 4 was more pronounced in Sema4AKO mice compared to wild-type mice.
The epidermis of Sema4AKO mice was significantly thicker than that of wild-type mice at 8 weeks of age.
Sema4AKO epidermis exhibited increased expression of Ccl20, Tnfα, and Il17a compared to wild-type epidermis.
The proportion of Vγ2+ T cells, double-negative (DN) γδ T cells, and IL-17A-producing cells of those fractions was increased in the epidermis of Sema4AKO mice compared to wild-type mice.
Upregulation of mTORC1 signaling was observed in the epidermis of both human psoriatic non-lesions and Sema4AKO mice.

Citações

"Sema4A-mediated signaling cascades can be triggers for psoriasis and targets in the treatment and prevention of psoriasis."
"Conclusively, Sema4A expression in keratinocytes plays a regulatory role in imiquimod-induced dermatitis."
"The epidermis of psoriatic non-lesion and Sema4AKO mice demonstrated mTOR complex 1 upregulation, and the application of mTOR inhibitors reversed the skewed expression of cytokeratins in Sema4AKO mice."

Principais Insights Extraídos De

Downregulation of Semaphorin 4A in keratinocytes reflects the features of non-lesional psoriasis

by Kume,M., Kog... às www.biorxiv.org 04-03-2024

https://www.biorxiv.org/content/10.1101/2024.04.02.587777v1

Perguntas Mais Profundas

What other signaling pathways or mechanisms, besides mTOR, might be involved in the regulation of keratinocyte differentiation and T17 cell infiltration in the context of Sema4A downregulation?

In addition to the mTOR pathway, several other signaling pathways and mechanisms could be implicated in the regulation of keratinocyte differentiation and T17 cell infiltration in the context of Sema4A downregulation. One key pathway is the NF-κB pathway, which is known to play a crucial role in the pathogenesis of psoriasis. NF-κB activation in keratinocytes leads to the production of pro-inflammatory cytokines and chemokines, contributing to the recruitment and activation of immune cells, including T17 cells. Downregulation of Sema4A could potentially dysregulate NF-κB signaling, exacerbating the inflammatory response in the skin.
Moreover, the JAK-STAT pathway is another important signaling cascade involved in immune responses and skin homeostasis. Dysregulation of JAK-STAT signaling in keratinocytes can lead to altered cytokine production and immune cell recruitment, further promoting the development of psoriatic features. Sema4A downregulation may impact the JAK-STAT pathway, influencing the differentiation of T17 cells and keratinocyte function.
Additionally, the Wnt/β-catenin pathway is essential for skin development and regeneration. Aberrant activation of this pathway can disrupt keratinocyte differentiation and barrier function, contributing to skin disorders like psoriasis. Sema4A downregulation may interact with the Wnt/β-catenin pathway, affecting epidermal homeostasis and immune cell infiltration in psoriatic skin.

What other skin or organ-specific functions of Sema4A could be explored to understand its broader implications in health and disease?

Beyond its role in psoriasis and immune regulation, Sema4A has diverse functions in various tissues and organs that warrant exploration to understand its broader implications in health and disease. In the context of skin biology, Sema4A may play a role in wound healing and tissue repair by modulating cell migration, proliferation, and angiogenesis. Understanding how Sema4A influences these processes could provide insights into skin regeneration and scar formation.
Moreover, Sema4A has been implicated in neurological disorders, where it acts as a guidance cue for axon guidance and neuronal development. Investigating the role of Sema4A in neurodevelopmental disorders, such as autism and schizophrenia, could uncover its impact on brain function and connectivity.
In the context of cancer, Sema4A has been associated with tumor progression and metastasis in various malignancies. Exploring the interactions between Sema4A and tumor microenvironment components could reveal its potential as a therapeutic target for cancer treatment.
Furthermore, Sema4A may have implications in cardiovascular health, as it has been linked to vascular development and endothelial cell function. Investigating the role of Sema4A in cardiovascular diseases, such as atherosclerosis and hypertension, could provide insights into its impact on vascular homeostasis and disease pathogenesis.
Overall, exploring the diverse functions of Sema4A in different tissues and organs can shed light on its multifaceted roles in health and disease, offering potential therapeutic avenues for a wide range of conditions beyond psoriasis.

How might the upregulation of Sema4A on immune cells, such as lymphocytes and monocytes, contribute to the pathogenesis of psoriasis, and could this be a potential therapeutic target?

The upregulation of Sema4A on immune cells, particularly lymphocytes and monocytes, can contribute to the pathogenesis of psoriasis by promoting pro-inflammatory responses and immune cell activation. Sema4A signaling in T cells has been shown to enhance Th17 differentiation and cytokine production, leading to the amplification of the inflammatory cascade in psoriatic lesions. Additionally, Sema4A expression on monocytes can modulate their activation and cytokine secretion, further fueling the inflammatory milieu in the skin.
Targeting the upregulated Sema4A signaling on immune cells could represent a promising therapeutic strategy for psoriasis. By inhibiting Sema4A-mediated pathways in lymphocytes and monocytes, it may be possible to dampen the exaggerated immune response and reduce the production of pro-inflammatory cytokines involved in psoriatic inflammation. This approach could help mitigate disease severity, reduce skin lesions, and improve patient outcomes.
Furthermore, blocking Sema4A signaling on immune cells could potentially modulate the immune microenvironment in psoriatic skin, leading to a more balanced immune response and decreased tissue damage. By targeting Sema4A as a therapeutic intervention, it may be possible to achieve better disease management and potentially prevent disease progression in individuals with psoriasis. Further research into the specific mechanisms of Sema4A action on immune cells is warranted to develop targeted therapies that can effectively modulate the immune dysregulation seen in psoriasis.