Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis
Yi Luan,
Jiajia Hu,
Qijun Wang,
Xujun Wang,
Wenxue Li,
Rihao Qu,
Chuan Yang,
Barani Kumar Rajendran,
Hongyue Zhou,
Peng Liu,
Ningning Zhang,
Yu Shi,
Yansheng Liu,
Wenwen Tang,
Jun Lu,
Dianqing Wu
Affiliations
Yi Luan
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA
Jiajia Hu
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA
Qijun Wang
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA
Xujun Wang
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
Wenxue Li
Yale Cancer Biology Institute, West Haven, CT 06516, USA
Rihao Qu
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA
Chuan Yang
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA
Barani Kumar Rajendran
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA
Hongyue Zhou
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA
Peng Liu
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA
Ningning Zhang
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
Yu Shi
School of Management, Yale University, New Haven, CT 06511, USA
Yansheng Liu
Yale Cancer Biology Institute, West Haven, CT 06516, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA; Corresponding author
Wenwen Tang
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA; Corresponding author
Jun Lu
Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Corresponding author
Dianqing Wu
Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA; Corresponding author
Summary: Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes.
