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

Francis M. Chen; Joyce K.Y. Tse; Leigang Jin; Chui Yiu Bamboo Chook; Fung Ping Leung; Gary Tse; Connie W. Woo; Aimin Xu; Ajay Chawla; Xiao Yu Tian; Ting Fung Chan; Wing Tak Wong

doi:10.7150/thno.67515

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

Francis M. Chen
, Joyce K.Y. Tse
, Leigang Jin
, Chui Yiu Bamboo Chook
, Fung Ping Leung
, Gary Tse
, Connie W. Woo
, Aimin Xu
, Ajay Chawla
, Xiao Yu Tian
, Ting Fung Chan
, Wing Tak Wong

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1161-1172
Number of pages	12
Journal	Theranostics
Volume	12
Issue number	3
DOIs	https://doi.org/10.7150/thno.67515
Publication status	Published - 2022
Externally published	Yes

Keywords

Alternatively activated macrophages
IL-13
IL-4
Left anterior descending coronary artery ligation
Neonatal heart regeneration
TH2 immunity

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10.7150/thno.67515

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@article{b6f12b41dbec4e89b3e29abc2b76b8c8,

title = "Type 2 innate immunity drives distinct neonatal immune profile conducive for heart regeneration",

abstract = "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.",

keywords = "Alternatively activated macrophages, IL-13, IL-4, Left anterior descending coronary artery ligation, Neonatal heart regeneration, TH2 immunity",

author = "Chen, \{Francis M.\} and Tse, \{Joyce K.Y.\} and Leigang Jin and Chook, \{Chui Yiu Bamboo\} and Leung, \{Fung Ping\} and Gary Tse and Woo, \{Connie W.\} and Aimin Xu and Ajay Chawla and Tian, \{Xiao Yu\} and Chan, \{Ting Fung\} and Wong, \{Wing Tak\}",

note = "Publisher Copyright: {\textcopyright} The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.",

year = "2022",

doi = "10.7150/thno.67515",

language = "English",

volume = "12",

pages = "1161--1172",

number = "3",

}

TY - JOUR

T1 - Type 2 innate immunity drives distinct neonatal immune profile conducive for heart regeneration

AU - Chen, Francis M.

AU - Tse, Joyce K.Y.

AU - Jin, Leigang

AU - Chook, Chui Yiu Bamboo

AU - Leung, Fung Ping

AU - Tse, Gary

AU - Woo, Connie W.

AU - Xu, Aimin

AU - Chawla, Ajay

AU - Tian, Xiao Yu

AU - Chan, Ting Fung

AU - Wong, Wing Tak

N1 - Publisher Copyright: © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Alternatively activated macrophages

KW - IL-13

KW - IL-4

KW - Left anterior descending coronary artery ligation

KW - Neonatal heart regeneration

KW - TH2 immunity

UR - https://www.scopus.com/pages/publications/85121913691

U2 - 10.7150/thno.67515

DO - 10.7150/thno.67515

M3 - Article

C2 - 35154480

AN - SCOPUS:85121913691

VL - 12

SP - 1161

EP - 1172

JO - Theranostics

JF - Theranostics

IS - 3

ER -

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

Abstract

Keywords

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