Rel B‐modified dendritic cells possess tolerogenic phenotype and functions on lupus splenic lymphocytes in vitro

Abstract

SummarySystemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by high morbidity and mortality and its treatment remains challenging. Dendritic cells (DCs) have been shown to participate in the initiation and perpetuation of lupus pathogenesis and the DCs that can induce tolerogenicity appear as potential cell‐based therapy in this condition. In this study, we examined the in vitro tolerogenic properties of bone‐marrow derived DCs (BMDCs) in the murine lupus setting. We used lentiviral transduction of RelB‐silencing short hairpin RNA to modify the expression of RelB, a key transcription factor regulating DC maturation, in BMDCs from MRL/MpJ mice. Tolerogenic properties of RelB‐modified DCs were compared with scrambled control (SC) ‐modified DCs. RelB expression was found to be significantly reduced in RelB‐modified DCs derived from MRL/MpJ mice, wild‐type of the same genetic background as MRL/lpr lupus‐prone mice. These MRL/MpJ RelB‐modified DCs displayed semi‐mature phenotype with expression of lower levels of co‐stimulatory molecules compared with SC‐modified DCs. RelB‐modified DCs were found to be low producers of interleukin‐12p70 (IL‐12p70) and could induce hyporesponsiveness of splenic T cells from MRL/MpJ and MRL/lpr mice. Furthermore, they down‐regulated interferon‐γ expression and induced IL‐10‐producing T cells in MRL/MpJ splenocytes, and attenuated interferon‐γ and IL‐17 expression in MRL/lpr splenic CD4+ lymphocytes. Splenocytes primed by RelB‐modified DCs demonstrated antigen‐specific suppressive effects on allogeneic splenocytes. In conclusion, RelB‐silencing in DCs generates DCs of tolerogenic properties with immunomodulatory function and appears as potential option of cell‐targeted therapy.

Transcription Factor Activity Inference in Systemic Lupus Erythematosus

“…On the other hand, RELB is a subunit of NF-κB and takes part in the development of dendritic cells [ 49 ]. In the murine lupus model, Relb-modified dendritic cells decreased the interferon-γ expression [ 50 ]. ARNTL is a TF that forms a core component of the circadian clock.…”

CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis

“…RelB is potentially translocated into the nucleus and activated when signal-induced noncanonical NF-κB kinase NIK degradation occurs (Sun, 2011). Recent evidence has revealed that disordered RelB in different cell types is generally associated with various autoimmune and inflammatory conditions, including IgA nephropathy (Jin et al, 2012), rheumatoid arthritis (Pettit et al, 2000), EAE (Ginwala et al, 2017), systemic lupus erythematosus (Wu et al, 2016), and psoriasis (Barton et al, 2000). However, to date, it remains largely unclear how RelB and the upstream kinase NIK are negatively regulated in myeloid cells.…”

Biological characteristics of transcription factor RelB in different immune cell types: implications for the treatment of multiple sclerosis

“…Currently, RelB-silenced tolerogenic DCs are used to study autoimmune diseases, such as systemic lupus erythematosus and myasthenia gravis. Moreover, significant protective effects have been observed in disease conditions [177][178][179]. In a very recent research, Andreas and his team found that mice with RelB-deficient DCs are almost resistant to induction of the EAE model because of the accumulation of FoxP3+ Tregs and the reduction of pathogenic T cells [180].…”