Adenosine Alleviates Necrotizing Enterocolitis by Enhancing the Immunosuppressive Function of Myeloid-Derived Suppressor Cells in Newborns

Dongmei Zhou, Meng Yao, Lijuan Zhang, Yingying Chen, Juan He, Yuxin Zhang, Haixu Xu, Pan Zhou, Wei Zhong, Zhi Yao and Jie Zhou
J Immunol July 1, 2022, ji2200142; DOI: https://doi.org/10.4049/jimmunol.2200142

Key Points

  • Adenosine significantly relieves the severity of NEC via regulating MDSCs.

  • Adenosine enhances the immunosuppressive and antibacterial activity of MDSCs.

  • Adenosine facilitates the migration of MDSCs to gut via CXCR2.

Abstract

Necrotizing enterocolitis (NEC) is a common disorder in premature infants that is characterized by hyperinflammation and severe necrosis in the intestine. The pathogenesis of NEC remains to be elucidated. In this study, we demonstrate that adenosine, a metabolite more abundant in infants than in adults, plays an important role in the prevention of NEC. Administration of adenosine or its analog, adenosine-5′-N-ethyluronamide (NECA), dramatically relieved the severity of NEC in neonatal mice. Meanwhile, adenosine treatment significantly enhanced the immunosuppressive function, antibacterial activity, and migration of myeloid-derived suppressor cells (MDSCs). However, depletion of MDSCs or inhibition of their migration using the CXCR2 inhibitor SB225002 almost completely abrogated the protective effect of adenosine on NEC. Mechanistic studies showed that MDSCs in newborns expressed abundant adenosine receptor A2B (A2BR) that elicits intracellular cAMP signaling and its downstream target NF-κB. Importantly, intestinal tissues from patients with NEC showed significantly lower infiltration of A2BR-positive MDSCs than those from healthy donors. These observations revealed that adenosine-induced MDSCs represent an essential immune axis for intestinal homeostasis in newborns.

Footnotes

  • This work was supported by National Natural Science Foundation of China Grants 81925018 and 82130049, the Start-Up Funding for High-Level Talents of Tianjin Medical University, and by Key Project of Tianjin Natural Science Foundation Grant 20JCZDJC00670 (all to J.Z.).

  • The online version of this article contains supplemental material.

  • Received February 18, 2022.
  • Accepted May 16, 2022.

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