Happy New Year from the Rothhammer Lab!
We had a great start into the new year and are pleased to share our two most recent publications!
A cell-based drug delivery platform for treating central nervous system inflammation
Oren Levy*, Veit Rothhammer*, Ivan Mascanfroni, Zhixiang Tong, Rui Kuai, Michael De Biasio, Qingping Wang, Tahir Majid, Christelle Perrault, Ada Yeste, Jessica E. Kenison, Helia Safaee, Juliet Musabeyezu, Martina Heinelt, Yuka Milton, Heidi Kuang, Haoyue Lan, William Siders, Marie-Christine Multon, Jonathan Rothblatt, Salam Massadeh, Manal Alaamery, Ali H. Alhasan, Francisco J. Quintana & Jeffrey M. Karp
J Mol Med (2021). https://doi.org/10.1007/s00109-020-02003-9
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases.
Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS
Rothhammer V, Kenison JE, Li Z, Tjon E, Takenaka MC, Chao CC, Alves de Lima K, Borucki DM, Kaye J, Quintana FJ.
Neurol Neuroimmunol Neuroinflamm. 2021. doi: 10.1212/NXI.0000000000000946.
Abstract
Objective: MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS.
Methods: We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes.
Results: We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia.
Conclusions: Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.