PGLYRP1-mIgG2a-Fc inhibits macrophage activation via AKT/NF-κB signaling and protects against fatal lung injury during bacterial infection

Summary Severe bacterial pneumonia leads to acute respiratory distress syndrome (ARDS), with a high incidence rate and mortality. It is well-known that continuous and dysregulated?macrophage activation is vital for aggravating the progression of pneumonia. Here, we designed and produced an antibody-like molecule, peptidoglycan recognition protein 1-mIgG2a-Fc (PGLYRP1-Fc). PGLYRP1 was fused to the Fc region of mouse IgG2a with high binding to macrophages. We demonstrated that PGLYRP1-Fc ameliorated lung injury and inflammation in ARDS, without affecting bacterial clearance. Besides, PGLYRP1-Fc reduced AKT/nuclear factor kappa-B (NF-κB) activation via the Fc segment bound Fc gamma receptor (FcγR)-dependent mechanism, making macrophage unresponsive, and immediately suppressed proinflammatory response upon bacteria or lipopolysaccharide (LPS) stimulus in turn. These results confirm that PGLYRP1-Fc protects against ARDS by promoting host tolerance with reduced inflammatory response and tissue damage, irrespective of the host’s pathogen burden, and provide a promising therapeutic strategy for bacterial infection.