The impact of cannabinoids on inflammasome signaling in HIV-1 infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) is a chronic disease that afflicts over 38 million people worldwide without a known cure. The advent of effective antiretroviral therapies (ART) has significantly decreased the morbidity and mortality associated with HIV-1 infection in people living with HIV-1 (PWH), thanks to durable virologic suppression. Despite this, people with HIV-1 experience chronic inflammation associated with co-morbidities. While no single known mechanism accounts for chronic inflammation, there is significant evidence to support the role of the NLRP3 inflammasome as a key driver. Numerous studies have demonstrated therapeutic impact of cannabinoids, including exerting modulatory effects on the NLRP3 inflammasome. Given the high rates of cannabinoid use in PWH, it is of great interest to understand the intersecting biology of the role of cannabinoids in HIV-1-associated inflammasome signaling. Here we describe the literature of chronic inflammation in people with HIV, the therapeutic impact of cannabinoids in PWH, endocannabinoids in inflammation, and HIV-1-associated inflammation. We describe a key interaction between cannabinoids, the NLRP3 inflammasome, and HIV-1 viral infection, which supports further investigation of the critical role of cannabinoids in HIV-1 infection and inflammasome signaling.

Keywords: HIV-1; cannabinoids; immune activation; infection; inflammasome.

Figure 1:

The role of cannabinoid receptor signaling in physiological functions and pathological states (left). Magnified image to the right is a schematic representation of the endocannabinoid system in the brain.  CB1R are expressed by presynaptic neurons and are activated by endocannabinoids, AEA and 2-AG. Calcium (Ca²⁺) influx into the presynaptic neuron leads to release of excitatory glutamate that either binds to postsynaptic receptors, NMDR or glutamate receptor, or gets taken up by glutamate transporters on astrocytes. CB1R agonists block glutamate release and excitotoxicity, which is linked to neuroinflammation. CB2R is predominantly expressed by microglia. CB2R agonists reduces neuroinflammation by blocking the production of proinflammatory cytokines.  Activation of selective purinergic receptor P2RX7 leads an increase in 2-AG production. Created with BioRender.com.

Figure 2:

A microglial cell is activated during acute HIV-1 infection and CBD and synthetic cannabinoids can modulate downstream signal transduction. A pyroptotic cell is shown nearby with extracellular ATP signaling through the P2RX7 receptor. Subsequent Ca2+ influx, coupled to toll-like receptor (TLR) signaling by lipopolysaccharide (LPS), activate the NLRP3 inflammasome. Activated NLRP3 inflammasome releases caspase-1 that cleaves precursor pro-IL-1b and pro-IL-18 to produce mature IL-1b and IL-18. Secretion of IL-1b and IL-18 lead to pyroptosis and inflammation. CBD and synthetic cannabinoids activate CB2R expressed by microglia and antagonize the NLRP3 inflammasome via P2RX7. Created with BioRender.com.