TY - JOUR

T1 - Cladribine inhibits secretion of pro-inflammatory cytokines and phagocytosis in human monocyte-derived M1 macrophages in-vitro

AU - Mathiesen, Caroline B. K.

AU - Rudjord-Levann, Asha M.

AU - Gad, Monika

AU - Larsen, Jesper

AU - Sellebjerg, Finn

AU - Pedersen, Anders Elm

PY - 2021

Y1 - 2021

N2 - Cladribine (Cd) is a purine nucleoside analogue which in an oral formulation is approved for treatment of patients with multiple sclerosis (MS). It is known to mediate the effect through a short-term selective reduction of lymphocytes with minimal effect on the innate immune system. However, a few studies have emerged, that also demonstrate a beneficial immunomodulatory effect of cladribine on monocyte-derived cells. As cladribine crosses the blood–brain barrier this effect could have clinical meaningful impact in the treatment of MS, where recruitment of innate cells such as M1 macrophages play a role in plaque development. Here, we investigated the in-vitro effect on monocyte differentiation into M1 and M2 macrophages and dendritic cells as well as the effect on activation of M1 macrophages. In our experiments, cladribine in therapeutic relevant in-vitro concentrations, did not lead to apoptosis in differentiated M1, M2 macrophages or DCs and did not interfere with the phenotype of these differentiated cells. In M1 macrophages, cladribine reduced the secretion of IL-6 and TNF-α observed after activation with LPS. Similar, cladribine reduced the phagocytic capacity of LPS activated M1 macrophages but did not affect unactivated cells. We conclude, that such reduction of inflammatory potential as well as reduced M1 phagocytic activity, e.g. within an MS plaque, could be an additional clinical meaningful effect of cladribine in the treatment of MS while at the same time it would leave M1 macrophages intact for the protection against infections.

AB - Cladribine (Cd) is a purine nucleoside analogue which in an oral formulation is approved for treatment of patients with multiple sclerosis (MS). It is known to mediate the effect through a short-term selective reduction of lymphocytes with minimal effect on the innate immune system. However, a few studies have emerged, that also demonstrate a beneficial immunomodulatory effect of cladribine on monocyte-derived cells. As cladribine crosses the blood–brain barrier this effect could have clinical meaningful impact in the treatment of MS, where recruitment of innate cells such as M1 macrophages play a role in plaque development. Here, we investigated the in-vitro effect on monocyte differentiation into M1 and M2 macrophages and dendritic cells as well as the effect on activation of M1 macrophages. In our experiments, cladribine in therapeutic relevant in-vitro concentrations, did not lead to apoptosis in differentiated M1, M2 macrophages or DCs and did not interfere with the phenotype of these differentiated cells. In M1 macrophages, cladribine reduced the secretion of IL-6 and TNF-α observed after activation with LPS. Similar, cladribine reduced the phagocytic capacity of LPS activated M1 macrophages but did not affect unactivated cells. We conclude, that such reduction of inflammatory potential as well as reduced M1 phagocytic activity, e.g. within an MS plaque, could be an additional clinical meaningful effect of cladribine in the treatment of MS while at the same time it would leave M1 macrophages intact for the protection against infections.

KW - Cladribine

KW - Macrophage

KW - Monocyte

KW - Multiple sclerosis

U2 - 10.1016/j.intimp.2020.107270

DO - 10.1016/j.intimp.2020.107270

M3 - Journal article

C2 - 33360830

AN - SCOPUS:85098157295

VL - 91

JO - International Immunopharmacology

JF - International Immunopharmacology

SN - 1567-5769

M1 - 107270

ER -