Spleen granulopoiesis in psoriasis immune microenvironment aggravates psoriasis via IL-6/P-STAT3 signaling.

Background: Psoriasis is an immune-mediated chronic inflammatory condition characterized by significant neutrophil infiltration in the skin. Given that the spleen is the largest peripheral immune organ in the body, it is important to investigate whether it has any impact on skin inflammation in psoriasis.

Methods: To investigate this mechanism, a psoriatic mouse model was established by IMQ application. Flow cytometry and immunohistochemistry analyses were performed to determine the percentage of various immune cells in the spleen. The role of neutrophils was specifically assessed using the anti-Gr-1 antibody. Splenic granulopoiesis was evaluated using EdU labeling. To understand the spleen's role in skin inflammation, splenectomy was performed on the experimental mice. IL-6 levels were measured by ELISA, and P-STAT3 in neutrophils was detected via immunofluorescence. Further examination of IL-6's effects on neutrophil formation involved treating mice with IL-6 antibody. The severity of psoriasis was evaluated through histological staining and PASI scoring.

Results: Our study revealed that the spleens of psoriatic mice were enlarged compared to those of vehicle mice. Among immune cell populations, neutrophils showed the most significant changes, with marked increases in both spleen and skin of psoriatic mice and patients, contributing to disease progression. Post-splenectomy, neutrophil infiltration in the skin was reduced by approximately 60% in psoriatic mice. This indicates that the neutrophils in the skin were primarily derived from the spleen. Additionally, the spleen showed a notable capacity for granulopoiesis with elevated neutrophils. Moreover, we found elevated IL-6 levels in the skin, blood, and spleen in the model, which was decreased after splenectomy. Treatment with an IL-6 antibody reduced neutrophil formation in both the spleen and skin, which alleviated skin inflammation in psoriatic mice. Additionally, P-STAT3 signaling was decreased following IL-6 antibody treatment. The neutrophil infiltration in spleen and skin was decreased after injection with the inhibitor of P-STAT3, which also alleviated the inflammation of psoriatic model. Thus, IL-6 served as the dominant regulator of spleen granulopoiesis, a process potentially mediated by P-STAT3 signaling.

Conclusions: The spleen plays a crucial role in the immune microenvironment of psoriasis as a major site of granulopoiesis, influencing neutrophil infiltration in the skin of psoriatic mice. Additionally, IL-6 is a key regulator of neutrophil formation in the spleen of psoriatic mice, likely through P-STAT3-dependent mechanisms.