PGLYRP1-mIgG2a-Fc inhibits macrophage activation via AKT/NF-κB signaling and protects against fatal lung injury during bacterial infection
Yan Jia,
Shan Ren,
Luyao Song,
Siyi Wang,
Wei Han,
Jingjing Li,
Yan Yu,
BuYong Ma
Affiliations
Yan Jia
Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
Shan Ren
Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Minhang District, Shanghai 200000, China
Luyao Song
Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
Siyi Wang
Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
Wei Han
Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
Jingjing Li
Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China; Corresponding author
Yan Yu
Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Minhang District, Shanghai 200000, China; Corresponding author
BuYong Ma
Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China; Corresponding author
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.
