# Role of Macrophages in Cardiac Remodeling: Cues From Zebrafish Heart

## TL;DR

This review explores how macrophage polarization affects heart regeneration and disease, comparing humans and zebrafish, and highlights potential therapies.

## Contribution

The paper provides a comprehensive overview of macrophage roles in cardiac remodeling and novel therapeutic strategies for heart repair.

## Key findings

- M1 macrophages contribute to fibrosis and scarring, while M2 macrophages aid in tissue restoration and regeneration.
- Modulating macrophage polarization through methods like microRNA and chemical agents shows promise for cardiac repair.
- Age-related changes in macrophage function influence regenerative capabilities in the heart.

## Abstract

Macrophages are a key component of innate immunity and regulate cardiac phenotypes by their polarization state. The classical M1 macrophages are activated by pro‐inflammatory stimuli, whereas M2 macrophages are activated by anti‐inflammatory stimuli. The balance between M1 and M2 polarization is important and tightly controlled to maintain tissue homeostasis.

This review aims to explain the diversity of the ability to regenerate among humans and zebrafish, the role of the immune system in heart regeneration, and macrophage function in normal conditions and disease. It also investigates age‐related effects on macrophage function and therapeutic strategies to manipulate macrophage polarization in the treatment of heart injury.

Systematic review of the literature was conducted focusing on macrophage polarization, cardiac regeneration mechanisms, and immunomodulatory therapy.

Macrophage polarization imbalances of M1‐M2 are involved in inflammatory and cardiac disease. Mechanisms of macrophage function under various states and in various species are useful for insightful comprehension of novel therapy strategies. Macrophage polarization modulation is a future potential strategy for cardiac repair and the treatment of cardiac disease.

Targeting macrophage polarization to restore balance and homeostasis is a promising strategy for supporting cardiac regeneration and the treatment of inflammatory cardiac disease.

The figure illustrates the role of macrophage polarization in cardiac damage and repair, highlighting monocyte to M0, M1, and M2 macrophage differentiation. M1 macrophages, in response to pro‐inflammatory cytokines (e.g., IFNγ, TNF‐α, IL‐6), are involved in fibrosis and scarring in the heart. M2 macrophages, in response to anti‐inflammatory cytokines (e.g., IL‐10, TGFβ), are involved in tissue restoration and regeneration. Various macrophage polarization modulating approaches to reverse scarring and support repair, such as microRNA modulation (e.g., miRNA‐98, miRNA‐21), chemical agents (e.g., Poly (I:C), Dapagliflozin), membrane potential manipulation (e.g., Glibenclamide), direct cardiac cell fate reprogramming, and cell‐based immunotherapies (e.g., CAR‐M and direct transplantation), are also highlighted.

We summarized the role of macrophages in cardiac remodeling.Macrophage polarization and their microenvironment g the fate of cardiac remodeling.Different regenerative capabilities, and how they are influenced by various factors such as age are explained.Possible therapeutic approaches for changing macrophage polarization to augment cardiac repair are highlighted.

We summarized the role of macrophages in cardiac remodeling.

Macrophage polarization and their microenvironment g the fate of cardiac remodeling.

Different regenerative capabilities, and how they are influenced by various factors such as age are explained.

Possible therapeutic approaches for changing macrophage polarization to augment cardiac repair are highlighted.