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

5 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

Access to Document

10.7150/thno.67515

Cite this

@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 - http://www.scopus.com/inward/record.url?scp=85121913691&partnerID=8YFLogxK

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

Access to Document

Other files and links

Fingerprint

Cite this