|Title||Rewiring of sIgM-mediated intracellular signaling through theCD180 Toll-like receptor|
|Authors||Porakishvili, N., Vispute, K., Rajakaruna, N., Kulikova, N., Tsertsvadze, T., Nathwani, A., Damle, R.N., Clark, E.A., Rai, K.R., Chiorazzi, N. and Lydyard, P.M.|
Chronic Lymphocytic Leukaemia (CLL) development and progression is thought to be driven by unknown antigens/autoantigens through the B cell receptor (BCR), and environmental signals for survival and expansion including Toll-like receptor (TLR) ligands. CD180/RP105, a membrane-associated orphan receptor of the TLR family, induces normal B cell activation and proliferation and is expressed by approximately 60% of CLL samples. Half of these respond to ligation with anti-CD180 antibody by increased activation/phosphorylation of protein kinases associated with BCR signaling. Hence CLL cells expressing both CD180 and the BCR could receive signals via both receptors. Here we investigated cross-talk between BCR and CD180-mediated signaling on CLL cell survival and apoptosis. Our data indicate that ligation of CD180 on responsive CLL cells leads to activation of either pro-survival BTK/PI3K/AKT-mediated, or pro-apoptotic p38MAPK-mediated signaling pathways, whilst sIgM ligation predominantly engages the BTK/PI3K/AKT pathway. Furthermore, pre-treatment of CLL cells with anti-CD180 redirects IgM-mediated signaling from the pro-survival BTK/PI3K/AKT towards the pro-apoptotic p38MAPK pathway. Thus pre-engaging CD180 could prevent further pro-survival signaling mediated via the BCR and, instead, induce CLL cell apoptosis, opening the door to therapeutic profiling and new strategies for the treatment of a substantial cohort of CLL patients.
|Keywords||CLL, TLRs, CD180, signalling|
|Journal citation||21, pp. 46-57|
|Publisher||Feinstein Institute for Medical Research|
|Digital Object Identifier (DOI)||doi:10.2119/molmed.2014.00265|
|Published||14 Jan 2015|