Synthetic cannabinoid WIN 55,212-2 reduces CHIKV replication, modulates cytokine and chemokine production, and induces ER stress-related transcriptional responses in human monocyte-derived macrophages.

Chikungunya virus (CHIKV), an emerging arbovirus of the family Togaviridae, causes Chikungunya fever (CHIKF), characterized by excessive inflammation and chronic arthralgia. Macrophages act as viral targets and amplifiers of inflammation, underscoring their crucial role in the pathogenesis of viral infections. Currently, no effective treatment exists for CHIKF, highlighting the need for novel therapeutic approaches. Cannabinoids, known for their immunomodulatory and antiviral properties, have emerged as potential candidates. Here, we investigated the effects of cannabidiol (CBD) and WIN 55,212-2 (WIN) in CHIKV-infected human monocyte-derived macrophages (MDMs). Pre- and post-treatment efficacy were assessed at 6- and 24-h post-infection (h.p.i). WIN, but not CBD, significantly reduced CHIKV replication in post-treatment assays, with effects most evident at 24 h.p.i. This antiviral activity occurred without significant changes in mRNA levels of IFNβ1, IFNλ1, and IL27p28, indicating that it did not alter the expression of type I/III interferons. Furthermore, WIN treatment reduced APOBEC3A mRNA levels. Additionally, WIN significantly reduced the production of CCL-2, as well as pro- (IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines, while upregulating IRE1α and sXBP1 transcripts, suggesting modulation of ER stress pathways. Overall, these findings identify WIN as a potential modulator of CHIKV replication and macrophage inflammatory response, acting through host-direct mechanisms that warrant further investigation.