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.

Inflammation is a physiological response composed by well-defined and overlapping events that can eliminate pathogens and reestablish homeostasis of tissues. Physiological systems have an elastic capacity to deal with numerous perturbations. Infection may lead to inflammation, tissue damage and disease as consequence of breakdown of tissue resilience. The resolutive phase is a sine qua non condition to achieve homeostasis after acute inflammation. Exuberant or chronic inflammation occurs in diverse infectious diseases. Pro-resolving molecules may be useful for the treatment of certain infections, as these molecules modulate the immune response and avoid the exacerbated/misplaced inflammation unleashed by microbes. Some pro-resolving molecules may also favour pathogen clearance, in addition to decreasing tissue damage. In this review, we discuss the endogenous role and the therapeutic potential of the most relevant pro-resolving molecules in the context of bacterial and viral infections.