| Summary: | Chikungunya (CHIKV) is an arthritogenic alphavirus that causes a self-limiting disease usually accompanied by joint pain and/or polyarthralgia with disabling characteristics. Immune responses developed during the acute phase of CHIKV infection determine the rate of disease progression and resolution. Annexin A1 (<i>AnxA1</i>) is involved in both initiating inflammation and preventing over-response, being essential for a balanced end of inflammation. In this study, we investigated the role of the <i>AnxA1-FPR2/ALX</i> pathway during CHIKV infection. Genetic deletion of <i>AnxA1</i> or its receptor enhanced inflammatory responses driven by CHIKV. These knockout mice showed increased neutrophil accumulation and augmented tissue damage at the site of infection compared with control mice. Conversely, treatment of wild-type animals with the <i>AnxA1</i> mimetic peptide (Ac<sub>2–26</sub>) reduced neutrophil accumulation, decreased local concentration of inflammatory mediators and diminished mechanical hypernociception and paw edema induced by CHIKV-infection. Alterations in viral load were mild both in genetic deletion or with treatment. Combined, our data suggest that the <i>AnxA1-FPR2/ALX</i> pathway is a potential therapeutic strategy to control CHIKV-induced acute inflammation and polyarthralgia.
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