Dopamine activates NF-κB and primes the NLRP3 inflammasome in primary human macrophages

Nolan, Rachel; Reeb, Katelyn L.; Rong, Yi; Matt, Stephanie; Johnson, Hannah S.; Runner, Kaitlyn; Gaskill, Peter J.

doi:10.1016/j.bbih.2019.100030

Cited by 32 publications

(33 citation statements)

References 218 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Drugs of abuse also exacerbate the effects of the HIV proteins trans-activator of transcription (Tat) and gp120 in inducing oxidative stress, microgliosis, and astrogliosis (Aksenov et al, 2001(Aksenov et al, , 2003Shah et al, 2013;Samikkannu et al, 2015;Zeng et al, 2018). Moreover, HIV Tat primes and activates proinflammatory responses in microglia via the NLR family pyrin domain containing 3 (NLRP3) inflammasome (Chivero et al, 2017), and dopamine can activate NF-κB and prime the NLRP3 inflammasome in macrophages (Nolan et al, 2020) (however, see Zhu et al, 2018). This could be exacerbated by drugs of abuse that promote dopamine transmission within areas of the brain that are particularly vulnerable to HIV, such as the striatum (Nolan and Gaskill, 2019).…”

Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

et al. 2021

View full text Add to dashboard Cite

Recent studies examining the neurobiology of substance abuse have revealed a significant role of neuroimmune signaling as a mechanism through which drugs of abuse induce aberrant changes in synaptic plasticity and contribute to substance abuse-related behaviors. Immune signaling within the brain and the periphery critically regulates homeostasis of the nervous system. Perturbations in immune signaling can induce neuroinflammation or immunosuppression, which dysregulate nervous system function including neural processes associated with substance use disorders (SUDs). In this review, we discuss the literature that demonstrates a role of neuroimmune signaling in regulating learning, memory, and synaptic plasticity, emphasizing specific cytokine signaling within the central nervous system. We then highlight recent preclinical studies, within the last 5 years when possible, that have identified immune mechanisms within the brain and the periphery associated with addiction-related behaviors. Findings thus far underscore the need for future investigations into the clinical potential of immunopharmacology as a novel approach toward treating SUDs. Considering the high prevalence rate of comorbidities among those with SUDs, we also discuss neuroimmune mechanisms of common comorbidities associated with SUDs and highlight potentially novel treatment targets for these comorbid conditions. We argue that immunopharmacology represents a novel frontier in the development of new pharmacotherapies that promote long-term abstinence from drug use and minimize the detrimental impact of SUD comorbidities on patient health and treatment outcomes.

show abstract

Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Substance abuse likely mediates these effects by dysregulating immune function and increasing HIV replication in CNS myeloid cells such as macrophages and microglia (17,18,(29)(30)(31)133), which are primary drivers of HIV neuropathogenesis (32)(33)(34)(35). Previous data from our lab shows that dopamine, which is increased by the use of all addictive substances, enhances both HIV infection and inflammatory cytokine production in primary human macrophages (50,(54)(55)(56)60). Infection of myeloid cells requires the chemokine receptor CCR5, and this receptor is also required for dopamine-mediated increases in HIV entry into these cells (55,83).…”

Section: Discussionmentioning

confidence: 84%

“…Treatment with IL-10 (50 ng/mL) was used as a positive control, as this cytokine increases CCR5 expression in human monocytes, macrophages, and microglia (79,102,103). This use of a positive control in hMDM is similar to what we and others have published (50,60,104), as there is considerable variation in the hMDM inflammatory response to environmental stimuli (105-107). Therefore, donors in which IL-10 did not increase CCR5 at 1 hour were excluded from the analysis.…”

Section: Dopamine Alters the Proportion Of Ccr5 Conformations In Hmdmmentioning

confidence: 88%

“…Exposure to dopamine concentrations induced by substance abuse increases HIV replication by increasing the number of infected macrophages (54)(55)(56). Further, dopamine has been shown to alter a variety of other functions that differ by cell type but include modulation of cytokine and chemokine secretion, changes in phagocytic activity, proliferation and chemotaxis (50,(57)(58)(59)(60).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

et al. 2021

View full text Add to dashboard Cite

Despite widespread use of antiretroviral therapy (ART), HIV remains a major public health issue. Even with effective ART many infected individuals still suffer from the constellation of neurological symptoms now known as neuroHIV. These symptoms can be exacerbated by substance abuse, a common comorbidity among HIV-infected individuals. The mechanism(s) by which different types of drugs impact neuroHIV remains unclear, but all drugs of abuse increase central nervous system (CNS) dopamine and elevated dopamine increases HIV infection and inflammation in human myeloid cells including macrophages and microglia, the primary targets for HIV in the brain. Thus, drug-induced increases in CNS dopamine may be a common mechanism by which distinct addictive substances alter neuroHIV. Myeloid cells are generally infected by HIV strains that use the chemokine receptor CCR5 as a co-receptor, and our data indicate that in a subset of individuals, drug-induced levels of dopamine could interfere with the effectiveness of the CCR5 inhibitor Maraviroc. CCR5 can adopt distinct conformations that differentially regulate the efficiency of HIV entry and subsequent replication and using qPCR, flow cytometry, Western blotting and high content fluorescent imaging, we show that dopamine alters the expression of specific CCR5 conformations of CCR5 on the surface of human macrophages. These changes are not affected by association with lipid rafts, but do correlate with dopamine receptor gene expression levels, specifically higher levels of D1-like dopamine receptors. These data also demonstrate that dopamine increases HIV replication and alters CCR5 conformations in human microglia similarly to macrophages. These data support the importance of dopamine in the development of neuroHIV and indicate that dopamine signaling pathways should be examined as a target in antiretroviral therapies specifically tailored to HIV-infected drug abusers. Further, these studies show the potential immunomodulatory role of dopamine, suggesting changes in this neurotransmitter may also affect the progression of other diseases.

show abstract

“…Based on the results of a joint analysis of transcriptomics and metabolomics, dopamine, γ-Aminobutyric acid, and leukotriene C4 were selected for further study. It had been shown that bacterial infection can cause a dopamine burst in the brain and Dopamine activates NF-κB and primes the NLRP3 in ammasome in primary human macrophages [68,69]. The study also unveiled that γ-Aminobutyric acid, the principal inhibitory neurotransmitter in the brain, has activation functions in the immune system [70].…”

Section: Discussionmentioning

confidence: 97%

Polypharmacology-based Approach for Screening of Traditional Chinese Medicinal extract and Multi-dimensional Targeting Verification

Xia

Wang

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Natural products and their unique polypharmacology offer significant advantages for finding novel therapeutics particularly for the treatment of complex diseases. Meanwhile, natural products in traditional Chinese medicine possess drug-like properties. In this study, we used the previously established co-infection model of Mycoplasma gallisepticum and Escherichia coli as a representative of complex diseases. The multi-omics joint analysis was used to reverse screen TCMs from the Chinese medicinal database and then targeted verification was conducted from multiple dimensions. Results: The results showed that the Chinese herbal compound screened by the target network played a good therapeutic effect in the case of co-infection. Furthermore, the four methods were performed at gene, protein, and metabolite levels, as well as molecular docking in vitro respectively, which were used to verify the multi-target therapeutic effect. Conclusions: These data suggest that we may provide a new method to validate target combinations of natural products that can be used to optimize their multiple structure-activity relationships to obtain drug-like natural product derivatives. Furthermore, the study could establish a new methodology for the research of Chinese herbal medicinal extract and provide a new multi-target treatment method for the occurrence of co-infection.

show abstract

Dopamine activates NF-κB and primes the NLRP3 inflammasome in primary human macrophages

Cited by 32 publications

References 218 publications

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

Polypharmacology-based Approach for Screening of Traditional Chinese Medicinal extract and Multi-dimensional Targeting Verification

Contact Info

Product

Resources

About