Contributions
Abstract: P557
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Bruton's tyrosine kinase (BTK) mediates B cell receptor (BCR) and Fc receptor (FcR) signaling. BTK inhibitors thus silence B cells and prevent innate immune activation via FcR, suggesting they may be beneficial for treating autoimmune diseases with B cell involvement. Furthermore, BTK has been implicated in mediating signaling of certain chemokine and cytokine receptors. The highly selective and irreversible BTK inhibitor evobrutinib inhibits disease development in an experimental autoimmune encephalomyelitis (EAE) model that is not amenable to B cell inhibition by anti-CD20 antibody, indicating that efficacy is mediated by effects beyond BCR. We therefore investigated the effect of BTK inhibition on the differentiation and activation of monocytes and macrophages, which may contribute to MS disease activity and progression.
GM-CSF has been shown to drive neuroinflammation in preclinical models for MS, and is crucial for the differentiation of pro-inflammatory M1 macrophages. In the studies reported herein we found that BTK is activated downstream of the GM-CSF receptor. In line with this finding, the in vitro GM-CSF differentiated M1 cells undergo apoptosis upon BTK inhibition. Monocytes treated with GM-CSF in the presence of BTK inhibitor secrete less TNF-α and express less IL-1ß, in addition to upregulating the expression of anti-inflammatory genes, such as IL-10. Furthermore, BTKi treatment increases the rate of phagocytosis by anti-inflammatory M2 Macrophages in vitro.
Our findings show that BTK inhibition hinders M1 macrophage differentiation and skews monocytes towards an anti-inflammatory M2 phenotype, while enhancing apoptotic cell uptake by the M2 cells. We therefore conclude that inhibiting BTK could have additional benefit in the treatment of MS and other autoimmune diseases, by targeting both B cells and myeloid cells simultaneously.
Disclosure: Yasemin Beguem Alankus: Employee of Merck KGaA; Roland Grenningloh: Employee of EMD Serono (a business of Merck KGaA); Philipp Haselmayer: Employee of Merck KGaA; Andrew Bender: Employee of EMD Serono (a business of Merck KGaA); Julia Bruttger: Employee of Merck KGaA
Abstract: P557
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Bruton's tyrosine kinase (BTK) mediates B cell receptor (BCR) and Fc receptor (FcR) signaling. BTK inhibitors thus silence B cells and prevent innate immune activation via FcR, suggesting they may be beneficial for treating autoimmune diseases with B cell involvement. Furthermore, BTK has been implicated in mediating signaling of certain chemokine and cytokine receptors. The highly selective and irreversible BTK inhibitor evobrutinib inhibits disease development in an experimental autoimmune encephalomyelitis (EAE) model that is not amenable to B cell inhibition by anti-CD20 antibody, indicating that efficacy is mediated by effects beyond BCR. We therefore investigated the effect of BTK inhibition on the differentiation and activation of monocytes and macrophages, which may contribute to MS disease activity and progression.
GM-CSF has been shown to drive neuroinflammation in preclinical models for MS, and is crucial for the differentiation of pro-inflammatory M1 macrophages. In the studies reported herein we found that BTK is activated downstream of the GM-CSF receptor. In line with this finding, the in vitro GM-CSF differentiated M1 cells undergo apoptosis upon BTK inhibition. Monocytes treated with GM-CSF in the presence of BTK inhibitor secrete less TNF-α and express less IL-1ß, in addition to upregulating the expression of anti-inflammatory genes, such as IL-10. Furthermore, BTKi treatment increases the rate of phagocytosis by anti-inflammatory M2 Macrophages in vitro.
Our findings show that BTK inhibition hinders M1 macrophage differentiation and skews monocytes towards an anti-inflammatory M2 phenotype, while enhancing apoptotic cell uptake by the M2 cells. We therefore conclude that inhibiting BTK could have additional benefit in the treatment of MS and other autoimmune diseases, by targeting both B cells and myeloid cells simultaneously.
Disclosure: Yasemin Beguem Alankus: Employee of Merck KGaA; Roland Grenningloh: Employee of EMD Serono (a business of Merck KGaA); Philipp Haselmayer: Employee of Merck KGaA; Andrew Bender: Employee of EMD Serono (a business of Merck KGaA); Julia Bruttger: Employee of Merck KGaA