Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages

Xin Yu; Yujing Song; Tao Dong; Wenlu Ouyang; Liujiazi Shao; Chao Quan; Kyung Eun Lee; Tao Tan; Allan Tsung; Katsuo Kurabayashi; Hasan B Alam; Mao Zhang; Jianjie Ma; Yongqing Li

doi:10.1172/jci.insight.181686

Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages

JCI Insight. 2024 Nov 22;9(22):e181686. doi: 10.1172/jci.insight.181686.

Authors

Xin Yu^{1

2}, Yujing Song^{3

4}, Tao Dong^{1

5}, Wenlu Ouyang^{1

6}, Liujiazi Shao^{1

7}, Chao Quan^{1

8}, Kyung Eun Lee⁹, Tao Tan⁹, Allan Tsung⁹, Katsuo Kurabayashi^{3

10}, Hasan B Alam¹¹, Mao Zhang², Jianjie Ma⁹, Yongqing Li¹

Affiliations

¹ Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
² Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
³ Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, New York, USA.
⁴ Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Department of Physiology, Xuzhou Medical University, Xu Zhou, Jiangsu, China.
⁶ Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Changsha, China.
⁷ Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Xicheng District, Beijing, China.
⁸ Department of Urology, The Xiangya Hospital, Changsha, China.
⁹ Department of Surgery, Division of Surgical Science, University of Virginia, Charlottesville, Virginia, USA.
¹⁰ Department of Chemical and Biomolecular Engineering, New York University, Brooklyn, New York, USA.
¹¹ Department of Surgery, Northwestern University, Arkes Pavilion, Chicago, Illinois, USA.

Abstract

Sepsis-induced acute lung injury (ALI) is prevalent in patients with sepsis and has a high mortality rate. Peptidyl arginine deiminase 2 (PADI2) and PADI4 play crucial roles in mediating the host's immune response in sepsis, but their specific functions remain unclear. Our study shows that Padi2-/- Padi4-/- double KO (DKO) improved survival, reduced lung injury, and decreased bacterial load in Pseudomonas aeruginosa (PA) pneumonia-induced sepsis mice. Using single-cell RNA-Seq (scRNA-Seq), we found that the deletion of Padi2 and Padi4 reduced the Nlrp3+ proinflammatory macrophages and fostered Chil3+ myeloid cell differentiation into antiinflammatory macrophages. Additionally, we observed the regulatory role of the NLRP3/Ym1 axis upon DKO, confirmed by Chil3 knockdown and Nlrp3-KO experiments. Thus, eliminating Padi2 and Padi4 enhanced the polarization of Ym1+ M2 macrophages by suppressing NLRP3, aiding in inflammation resolution and lung tissue repair. This study unveils the PADIs/NLRP3/Ym1 pathway as a potential target in treatment of sepsis-induced ALI.

Keywords: Bacterial infections; Immunology; Inflammation; Macrophages; Surgery.

MeSH terms

Acute Lung Injury* / etiology
Acute Lung Injury* / immunology
Acute Lung Injury* / pathology
Animals
Disease Models, Animal
Macrophages* / immunology
Macrophages* / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout*
NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
Protein-Arginine Deiminase Type 2* / metabolism
Protein-Arginine Deiminase Type 4* / metabolism
Pseudomonas aeruginosa
Sepsis* / complications
Sepsis* / immunology

Substances

Protein-Arginine Deiminase Type 4
NLR Family, Pyrin Domain-Containing 3 Protein
Protein-Arginine Deiminase Type 2
peptidylarginine deiminase 4, mouse
Padi2 protein, mouse
Nlrp3 protein, mouse

Grants and funding

R01 HL155116/HL/NHLBI NIH HHS/United States