SPHK2-Generated S1P in CD11b+ Macrophages Blocks STING to Suppress the Inflammatory Function of Alveolar Macrophages
Jagdish C. Joshi,
Bhagwati Joshi,
Ian Rochford,
Sheikh Rayees,
Md Zahid Akhter,
Sukriti Baweja,
Koteshwara Rao Chava,
Mohammad Tauseef,
Hazem Abdelkarim,
Viswanathan Natarajan,
Vadim Gaponenko,
Dolly Mehta
Affiliations
Jagdish C. Joshi
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA
Bhagwati Joshi
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA
Ian Rochford
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA
Sheikh Rayees
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA
Md Zahid Akhter
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA
Sukriti Baweja
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA
Koteshwara Rao Chava
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA
Mohammad Tauseef
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA
Hazem Abdelkarim
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois, Chicago, IL, USA
Viswanathan Natarajan
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA; Department of Medicine, College of Medicine, University of Illinois, Chicago, IL, USA
Vadim Gaponenko
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois, Chicago, IL, USA
Dolly Mehta
Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL, USA; Corresponding author
Summary: Acute lung injury (ALI) is a lethal inflammatory lung disorder whose incidence is on the rise. Alveolar macrophages normally act to resolve inflammation, but when dysregulated they can provoke ALI. We demonstrate that monocyte-derived macrophages (CD11b+ macrophages) recruited into the airspace upregulate the anti-inflammatory function of alveolar macrophages by suppressing their stimulator of type 1 interferon gene (STING) signaling. Depletion of CD11b+ macrophages in mice (macrophagedep mice) after endotoxin or after Pseudomonas aeruginosa causes expansion of the inflammatory alveolar macrophage population, leading to neutrophil accumulation, irreversible loss of lung vascular barrier function, and lethality. We show that CD11b+ macrophages suppress alveolar macrophage-STING signaling via sphingosine kinase-2 (SPHK2) generation of sphingosine-1-phosphate (S1P). Thus, adoptive transfer of wild-type (WT) or STING−/−, but not SPHK2−/−, CD11b monocytes from murine bone marrow into injured macrophagedep mice rescue anti-inflammatory alveolar macrophages and reverse lung vascular injury. SPHK2-induced S1P generation in CD11b+ macrophages has the potential to educate alveolar macrophages to resolve ALI. : Joshi et al. demonstrate an essential role of SPHK2+ monocyte-derived CD11b+ macrophages, which are recruited to the airspace, in promoting anti-inflammatory function of alveolar macrophages during lung injury. They show that S1P generated by recruited SPHK2+-CD11b+ macrophages suppresses STING signaling in alveolar macrophages to resolve inflammatory injury. Keywords: acute lung injury, sting, sphingosine kinase 2, alveolar macrophages, recruited macrophages, CD11b+ macrophages, S1P, inflammation, cGAMP
