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 (Ac_2–26) 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.

Eosinophils are abundant in the reproductive tract, contributing to the remodeling and successful implantation of the embryo. However, the mechanisms by which eosinophils migrate into the uterus and their relationship to edema are still not entirely clear, since there are a variety of chemotactic factors that can cause migration of these cells. Therefore, to evaluate the role of CCR3 in eosinophil migration, ovariectomized C57BL/6 mice were treated with CCR3 antagonist SB 328437 and 17β-estradiol. The hypothesis that the CCR3 receptor plays an important role in eosinophil migration to the mouse uterus was confirmed, because we observed reduction in eosinophil peroxidase activity in these antagonist-treated uteruses. The antagonist also influenced uterine hypertrophy, inhibiting edema formation. Finally, histological analysis of the orcein-stained uteruses showed that the antagonist reduced eosinophil migration together with edema. These data showed that the CCR3 receptor is an important target for studies that seek to clarify the functions of these cells in uterine physiology.

Accumulating evidence supports pro-resolving actions of the Plasminogen/Plasmin (Plg/Pla) system during inflammation, beyond its classical role in fibrin degradation. Here, we investigated the role of Plg/Pla on key features of inflammation resolution in a murine model of severe pneumococcal pneumonia. High levels of Plg were observed in the airways following infection, accompanied by increased levels of plasminogen activator inhibitor-1, neutrophil elastase and Plg degradation fragments as inflammation progressed. Pla treatment of mice infected with Streptococcus pneumoniae (Sp) decreased neutrophilic infiltration in airways and lungs, accompanied by lower concentrations of the neutrophil chemoattractive chemokines CXCL1 and CXCL2, as well as the pro-inflammatory cytokines TNF, IL-6, and IL-1β. Pla-treatment also enhanced neutrophil apoptosis and efferocytosis, and slightly reduced bacterial loads in bronchoalveolar lavage. In addition, Pla decreased damage and fibrin deposition in lungs, improving pneumonia-driven pulmonary mechanical dysfunction, and rescuing mice from lethality. Pla-induced resolution of Sp-evoked inflammation was associated with neutrophil apoptosis, as the caspase-3 specific inhibitor Z-DEVD-FMK blocked Pla protective actions. In addition to the effects on neutrophils, intranasal instillation of Pla in naïve mice increased the number of alveolar macrophages and guided them toward a regulatory phenotype marked by enhanced efferocytosis of apoptotic neutrophils and increased bacterial phagocytosis, ultimately promoting host protection against pneumococcus-induced inflammation and tissue damage. In sum, our findings demonstrate that plasmin modulates the lung inflammatory milieu and promotes key pro-resolving events, namely neutrophil apoptosis and expansion of alveolar macrophage with enhanced efferocytosis and phagocytic abilities, resulting in improved lung function and survival in pneumococcal pneumonia.

Biochanin A (BCA), a phytoestrogen with broad therapeutic potential, is a promising molecule for alleviating post-menopausal symptoms and treating disorders related to reproductive metabolism. Nevertheless, the effect of BCA on inflammatory changes caused by postmenopausal obesity is unclear. Thus, this study focused on investigating the impact of BCA on the adipose tissue and liver of ovariectomized (OVX) mice subjected to a high-fat diet (HFD). We found that BCA treatment reduced the crown-like structures (CLS), adipocyte area, and hypertrophic adipocyte distribution. This was accompanied by an increase in the anti-inflammatory cytokines interleukin (IL)-5 and IL-10 and the expression of Mrc1 (CD206), a marker for M2 macrophages. Furthermore, there was a reduction in the extent of hepatic steatosis, triglyceride content, and the expression of Nos2, the M1 marker. We concluded that BCA exerted an anti-inflammatory response in the tissues, promoting a resolving profile, although the metabolic profile of the animals was not altered. This study was the first to demonstrate the anti-inflammatory effect of BCA in ovariectomized animals with established obesity.

Background and Purpose: Rheumatoid Arthritis is an inflammatory disease characterized by joint inflammation and pain. An emerging therapeutic approach for the treatment of inflammation involves targeting the resolution phase of inflammation using pro-resolving mediators, which activate endogenous protective mechanisms. Ac2-26, a mimetic peptide derived from the sequence of annexin A1 (a pro-resolving mediator), has shown efficacy in the treatment of inflammatory disorders. However, its therapeutic potential is limited by rapid clearance and poor aqueous solubility. In this study, we investigated whether a novel formulation of Ac2-26 included in hydroxypropyl-β-cyclodextrin (Ac/HPβ-CD) could potentiate its pro-resolving efficacy compared to the free peptide in an antigen-induced arthritis model induced in mice. Experimental Approach: Arthritic BALB/c mice were treated with either free Ac2-26 or Ac/HPβ-CD at doses 150, 50 and 15 µg per mouse (i.p.) at the peak of inflammation. Leukocyte recruitment, neutrophil apoptosis and efferocytosis were determined by knee joint wash cell morphology counting and flow cytometry. Cytokine levels were quantified by ELISA. Mechanical hypernociception was assessed using an electronic von Frey aesthesiometer. MerTK and CD47 expression were determined by flow cytometry. Key Results: Here, we showed that Ac/HPβ-CD at a dose of 50 μg/mouse was sufficient to resolve joint inflammation, whereas free peptide achieved comparable effects only at the highest tested dose. Ac/HPβ-CD increase the expression of full-length AnxA1, reduced accumulated neutrophils within knee joint, decreased levels of CXCL1 and IL-1β in periarticular tissues, as well as reduced histological scores and pain. Importantly, the reduction in neutrophil survival was linked to enhanced apoptosis and MertK-mediated efferocytosis, along with decreased expression of CD47, a “don’t-eat-me” signal. Conclusions & Implications: These results demonstrate that inclusion of Ac2-26 in HPβ-CD enhances its potency at lower doses and may represent a promising therapeutic strategy to promotes the inflammation resolution.