Teriflunomide and monomethylfumarate target HIV-induced neuroinflammation and neurotoxicity

Abstract

HIV-associated neurocognitive disorders (HAND) affect about 50% of infected patients despite combined antiretroviral therapy (cART). Ongoing compartmentalized inflammation mediated by microglia which are activated by HIV-infected monocytes has been postulated to contribute to neurotoxicity independent from viral replication. Here, we investigated effects of teriflunomide and monomethylfumarate on monocyte/microglial activation and neurotoxicity. Human monocytoid cells (U937) transduced with a minimal HIV-Vector were co-cultured with human microglial cells (HMC3). Secretion of pro-inflammatory/neurotoxic cytokines (CXCL10, CCL5, and CCL2: p < 0.001; IL-6: p < 0.01) by co-cultures was strongly increased compared to microglia in contact with HIV-particles alone. Upon treatment with teriflunomide, cytokine secretion was decreased (CXCL10, 3-fold; CCL2, 2.5-fold; IL-6, 2.2-fold; p < 0.001) and monomethylfumarate treatment led to 2.9-fold lower CXCL10 secretion (p < 0.001). Reduced toxicity of co-culture conditioned media on human fetal neurons by teriflunomide (29%, p < 0.01) and monomethylfumarate (27%, p < 0.05) indicated functional relevance. Modulation of innate immune functions by teriflunomide and monomethylfumarate may target neurotoxic inflammation in the context of HAND.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0829-2) contains supplementary material, which is available to authorized users.

The human microglial HMC3 cell line: where do we stand? A systematic literature review

“…In addition, it has been shown that the HMC3 cells (provided by Dr. J Pocock, University College of London) produce significant amounts of IL-6, together with several chemokines (i.e., CXCL10, CCL5, and CCL2) in response to human immunodeficiency virus (HIV) vector-transduced monocytoid cells (HIV-U937 cells). HMC3 microglial cells in contact with HIV vector alone responded with increased production of IL-6, CXCL10, and CCL5, albeit to a lower extent in comparison to activation with HIV-U937 cells [30]. Data presented in this paper confirm a basal production of IL-6 in HMC3 cells, together with sizable amounts of CCL5.…”

“…Data presented in this paper confirm a basal production of IL-6 in HMC3 cells, together with sizable amounts of CCL5. Other cytokines, including IFNγ, IL-1β, IL-4, and IL-10 were not detected [30]. The immunomodulating agent, teriflunomide, significantly reduced microglial inflammatory activation induced by HIV-U937 cells, whereas, monomethylfumarate (MMF) was less effective (only CXCL10 reduction at the highest dose tested).…”

“…Interestingly, data obtained with the HMC3 cells were confirmed in primary cultures of human microglial cells (isolated from patients with intractable epilepsy), thus further supporting the relevance of this experimental model to study human microglial properties. Conditioned medium harvested from HMC3 cells exposed to HIV transduced monocytoid cells caused significant neuronal toxicity, whereas neuroprotection was observed with teriflunomide and MMF treatments [30]. However, Rawat and collaborators [59] questioned the use of human microglial cell lines, including the HMC3 cells, for the study of HIV pathogenesis due to the genetic manipulation caused by the immortalization procedure, the higher growth rate in comparison to primary microglial cells, and reduced HIV replication within these cells.…”

“…The cell line is distributed by ATCC® under the catalog designation of HMC3 (ATCC®CRL-3304). Interestingly, a PubMed search (database accessed on June 4, 2018), using (HMC3) OR (HMC-3) as keywords retrieved 24 papers, among which only seven are indeed articles related to the human microglial HMC3 cell line, i.e., six original studies [20,21,[29][30][31][32] and one review article [22]. Two of these original papers are also included in the reference list reported in the HMC3 (ATCC®CRL-3304) cell line's data sheet [20,21].…”

Optogenetic manipulation of astrocytes from synapses to neuronal networks: A potential therapeutic strategy for neurodegenerative diseases

“…Guo et al () injected a retrovirus under the control of GFAP promoter in adult mouse cortex to specifically express NeuroD1, which is essential for adult neurogenesis (Gao et al, ; Zhang et al, ), in activated astrocytes. It is worth to mention that retroviruses only infect dividing cells such as progenitor cells or reactive glial cells (Ambrosius et al, ; Zhao, Teng, Summers, Ming, & Gage, ). NeuroD1‐expressing astrocytes can reprogram into glutamatergic neurons in AD mouse model and cultured human astrocytes in vitro (Guo et al, ).…”