Annexin A1-FPR2/ALX Signaling Axis Regulates Acute Inflammation during Chikungunya Virus Infection

Abstract

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 (AnxA1) 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 AnxA1-FPR2/ALX pathway during CHIKV infection. Genetic deletion of AnxA1 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 AnxA1 mimetic peptide (Ac2–26) 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 AnxA1-FPR2/ALX pathway is a potential therapeutic strategy to control CHIKV-induced acute inflammation and polyarthralgia.

Annexin A1, A2, A5, and A6 involvement in human pathologies

“…In its complex with the S100A11 protein, it exerts diverse anti-inflammatory responses to pathogens through the FPR2 receptor pathway. 115,116 It inhibits proinflammatory phospholipase action and modifies leukocyte extravasation, apoptosis, cytokine release, and tumor invasion. 117 AnxA1 regulates neutrophil migration to sites of inflammation as well as the apoptosis of neutrophils which have a very short circulation life.…”

“…It inhibits pro‐inflammatory phospholipase action and modifies leukocyte extravasation, apoptosis, cytokine release, and tumor invasion 117 . AnxA1 regulates neutrophil migration to sites of inflammation as well as the apoptosis of neutrophils which have a very short circulation life 116 …”

The Multifaceted Role of Annexin A1 in Viral Infections

“…Overall, the AnxA1 pathway appears to be beneficial for controlling excessive inflammation and hypernocyception in arboviral diseases, without affecting the ability of the host to fight infection [ 24 , 26 ]. Short-term systemic glucocorticoids have been successfully used to treat chronic rheumatic manifestations caused by CHIKV.…”

“…Interestingly, the AnxA1 mimetic peptide, Ac2-26, has been shown to effectively reduce inflammation and edema, as well as provide an analgesic effect via the activation of the FPR2 receptor in CHIKV infection. This suggests that targeting the AnxA1/FPR2 pathway might be beneficial in managing Chikungunya fever (CHIKF) and its associated arthritis [ 26 , 124 ].…”

“…Throughout previous years, our group has been exploring the idea of dissociating the components of the host immune system that can fight pathogens, from the components that cause excessive inflammation, which can be life-threatening [ 22 , 23 , 24 , 25 , 26 ]. This dissociation has, as one of its central players, the modulation of AnxA1 signaling and its membrane receptor, formyl Peptide Receptor 2 (FPR2).…”