Modulating macrophage phenotypes as a therapeutic strategy in neurodegenerative diseases
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- Institutt for biologi 
Macrophages are sentinel cells and are responsible for maintaining homeostasis in tissues and balancing the expression of proinflammatory versus anti-inflammatory factors. In the central nervous system (CNS), the balance of brain macrophage phenotypes underlies the inflammatory gene expression and clearance of toxic extracellular protein aggregates. Chronic expression of inflammatory genes and accumulation of amyloid beta (A) have been implicated in many studies as prospective etiologies of neurodegenerative diseases such as NeuroHIV and Alzheimer s disease (AD). Hence, manipulating brain macrophage phenotypes may represent a promising therapeutic strategy for neurodegenerative diseases. Cannabinoid (CB) receptor agonists reverse the neurodegenerative process in many transgenic animal models for neurodegenerative diseases and are associated with therapeutic effects in humans. These discoveries predicate the following hypotheses: a CB receptor agonist, WIN55,212-2 (WIN), will 1) block induction of the proinflammatory and neurotoxic phenotype and 2) reduce HIV-infection efficiency in macrophages (MDMS). To model perivascular macrophages, peripheral blood mononuclear cells (PBMC) were differentiated into monocyte derived macrophages (MDMs). The MDMs were treated with WIN for 24 hours before exposure to the proinflammatory cytokine IL-1 or recombinant A 1-42 for an additional 24 hours. MDMs were next analyzed for expression of proinflammatory (IL-1 and IFN-) and anti-inflammatory (Triggering receptor expressed on myeloid [TREM] 2) genes. To test neurotoxicity of activated MDMs and the neuroprotective potential of WIN, primary human neurons were treated with conditioned media (CM) from all treatment groups and analyzed for neuronal morphology and integrity by Microtubule-associated protein (MAP) 2 immunostaining. To determine effects of a CB receptor agonist on HIV replication efficiency, HIV-infected MDMs were treated with WIN and then analyzed for the expression of HIV capsid protein, p24. IL-1 reduced expression of TREM2, and increased IL-1 and IFN- in MDMs; however, pretreatment of MDMs with WIN reversed these changes. MDMs pretreated with WIN had more elongated morphology compared to vehicle-treated cells, indicating the anti-inflammatory phenotype. CM from MDMs exposed to WIN resulted in a higher level of MAP2 in primary human neurons than CM from IL-1-treated MDMs. Lastly, HIV+ MDMs pretreated with WIN produced lower levels of p24 compared to vehicle-treated MDMs. These results suggest that CB receptor agonists may be used to modulate phenotype and reduce HIV-replication efficiency in macrophages. These findings identify a novel role for CB receptor agonists to reduce neurotoxicity in NeuroHIV and other neurodegenerative disease.