INDOMETHACIN REDUCES HOMING AND MIGRATION GENE EXPRESSION IN INFLAMMATORY LANGERHANS LIKE DENDRITIC CELLS

MARÍA CATALINA LAVA; CINTHIA MARIEL OLEXEN; DENISE MARIEL RISNIK; DIEGO ALFREDO ROSSO; EUGENIO A CARRERA SILVA; ANDREA E ERRASTI

Estocolmo

Congreso; 38th Annual Meeting of the Histiocyte Society; 2022

Histiocyte Society

Purpose: Indomethacin, a non-selective COX inhibitor, has proven to be an effective treatment for patients with skeletal manifestations of Langerhans cell Histiocytosis (LCH). Nevertheless, the specific mechanism leading to the clinical improvement of this drug in LCH has not yet been established. We hypothesize that indomethacin can affect the homing to the bone in Langerhans cells (LC) and their precursors. Methods: In the current work, we evaluated the expression of homing and migration molecules in sorted circulating mononuclear myeloid cells of patients with LCH and healthy controls by qPCR and flow cytometry. To dissect the effect of indomethacin on the expression of homing related genes, we standardized an in-vitro inflammatory Langerhans like dendritic cells “LC-like” model (IL-4 plus GM-CSF plus TGF plus TNF plus dexamethasone) from control CD14 monocytes in contrast to conventional dendritic cells (GM-CSF plus IL-4) in the absence and presence of indomethacin (30 to 100 uM).Results: We have found that AXL, a tyrosine kinase receptor involved in cancer cell migration, is significantly increased in patients with LCH (N=13, P=0.01) and particularly higher in bone compromise (N=6, P=0.0001). Furthermore, sorted myeloid cells of patients with bone LCH have increased expression of CCR6 (N=6), a chemokine receptor which higher expression is associated with homing to the bone. In addition, in-vitro inflammatory LC-like cells were characterized by high levels of AXL, CXCR4 and CCR6, compared to conventional dendritic cells. We have found that in vitro indomethacin treatment of this inflammatory “LC-like” significantly reduced AXL receptor expression (N=6, P=0.03), and decreased the inflammatory cytokine TNF, and the chemokine receptor CCR6. Conclusion: Our results suggest that indomethacin could be affecting the homing of LCH precursors to the bone and consequently reducing tissue damage.