Annexin A1/FPR2 pathway modulates leukocyte function during Escherichia coli‐induced pneumonia to promote resolution of inflammation and restores lung function

BACKGROUND AND PURPOSE: Gram-negative bacteria are the main causes of pneumonia in the nosocomial environment. Inflammation triggered during pneumonia is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data shows that annexin A1 (ANXA1) signalling through its receptor FPR2 promotes host resistance and resilience in preclinical models of infectious disease. EXPERIMENTAL APPROACH: Using a mouse model of Escherichia coli-induced pneumonia, the role of ANXA1/FPR2 on key steps of inflammation resolution was evaluated. KEY RESULTS: Anxa1 and Fpr2/3 knockout mice, intranasally infected with E. coli, exhibited exacerbated neutrophilic inflammation, higher bacterial dissemination, decreased neutrophil apoptosis/efferocytosis counts in the airways and higher levels of inflammatory cytokines/chemokines coupled to marked lung damage and dysfunction, as compared to WT mice. Treatment of WT-infected mice with the ANXA1 peptidomimetic, annexin I-(2-26), decreased inflammation, increased apoptosis/efferocytosis of neutrophils and improved bacterial clearance in the airways and lungs, resulting in an improvement of lung function. The pan-caspase inhibitor Z-VAD-FMK prevented annexin I-(2-26)-induced resolution of the neutrophilic inflammation, underlining neutrophil apoptosis as the main mechanism for annexin I-(2-26) promotion of resolution of E. coli pneumonia. In addition, annexin I-(2-26) treatment increased the numbers of airway macrophages of infected mice and promoted macrophage phagocytosis of E. coli in vitro. CONCLUSIONS AND IMPLICATIONS: In summary, these findings highlight the role for ANXA1/FPR2 pathway as a nonredundant resolution mechanism for E. coli-induced pneumonia and demonstrate that annexin I-(2-26) as a potential host-directed therapeutic approach to treat infectious lung diseases.