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Type 2 innate immunity drives distinct neonatal immune profile conducive for heart regeneration

Chen, Francis M., Tse, Joyce KY, Jin, Leigang, Chook, Chui Yiu Bamboo, Leung, Fung Ping, Tse, Gary, Woo, Connie W., Xu, Aimin, Chawla, Ajay, Tian, Xiao Yu, and others. (2022) Type 2 innate immunity drives distinct neonatal immune profile conducive for heart regeneration. Theranostics, 12 (3). pp. 1161-1172. ISSN 1838-7640. (doi:10.7150/thno.67515) (KAR id:98238)


Aims: Neonatal immunity is functionally immature and skewed towards a TH2-driven, anti-inflammatory profile. This neonatal immunotolerance is partly driven by the type 2 cytokines: interleukin-4 (IL-4) and interleukin-13 (IL-13). Studies on neonatal cardiac regeneration reveal the beneficial role of an anti-inflammatory response in restoring cardiac function after injury. However, the role of an imbalanced immune repertoire observed in neonates on tissue regeneration is poorly understood; specifically, whether IL-4 and IL-13 actively modulate neonatal immunity during cardiac injury.

Methods and results: Neonatal mice lacking IL-4 and IL-13 (DKOs) examined at 2 days after birth exhibited reduced anti-inflammatory immune populations with basal cardiac immune populations like adult mice. Examination of neonates lacking IL-4 and IL-13 at 2 days post cardiac ischemic injury, induced on the second day after birth, showed impaired cardiac function compared to their control counterparts. Treatment with either IL-4 or IL-13 cytokine during injury restored both cardiac function and immune population profiles in knockout mice. Examination of IL-4/IL-13 downstream pathways revealed the role of STAT6 in mediating the regenerative response in neonatal hearts. As IL-4/IL-13 drives polarization of alternatively activated macrophages, we also examined the role of IL-4/IL-13 signaling within the myeloid compartment during neonatal cardiac regeneration. Injury of IL-4Rα myeloid specific knockout neonates 2 days after birth revealed that loss of IL-4/IL-13 signaling in macrophages alone was sufficient to impair cardiac regeneration.

Conclusions: Our results confirm that the TH2 cytokines: IL-4 and IL-13, which skews neonatal immunity to a TH2 profile, are necessary for maintaining and mediating an anti-inflammatory response in the neonatal heart, in part through the activation of alternatively activated macrophages, thereby permitting a niche conducive for regeneration.

Item Type: Article
DOI/Identification number: 10.7150/thno.67515
Projects: 14101119
Uncontrolled keywords: IL-4, IL-13, neonatal heart regeneration, TH2 immunity, alternatively activated macrophages, left anterior descending coronary artery ligation
Subjects: R Medicine
Divisions: Divisions > Division of Natural Sciences > Kent and Medway Medical School
Depositing User: Suzanne Duffy
Date Deposited: 22 Nov 2022 16:13 UTC
Last Modified: 23 Nov 2022 16:14 UTC
Resource URI: (The current URI for this page, for reference purposes)

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