Neutrophils in Tissue Injury and Repair: Molecular Mechanisms and Therapeutic Targets

Abstract

Tissue repair represents a highly intricate and ordered dynamic process, critically reliant on the orchestration of immune cells. Among these, neutrophils, the most abundant leukocytes in the body, emerge as the initial immune responders at injury sites. Traditionally recognized for their antimicrobial functions in innate immunity, neutrophils now garner attention for their indispensable roles in tissue repair. This review delves into their novel functions during the early stages of tissue injury. We elucidate the mechanisms underlying neutrophil recruitment and activation following tissue damage and explore their contributions to vascular network formation. Furthermore, we investigate the pivotal role of neutrophils during the initial phase of repair across different tissue types. Of particular interest is the investigation into how the fate of neutrophils influences overall tissue healing outcomes. By shedding light on these emerging aspects of neutrophil function in tissue repair, this review aims to pave the way for novel strategies and approaches in future organ defect repair, regeneration studies, and advancements in tissue engineering. The insights provided here have the potential to significantly impact the field of tissue repair and regeneration.

Keywords: angiogenesis; neutrophils; neutrophils fate; polarization; tissue repair.

FIGURE 1

The role of neutrophils in tissue repair. Using bone tissue injury repair as an example: (1) After tissue injury, damaged cells release damage‐associated molecular patterns (DAMPs), which directly recruit neutrophils and induce local macrophages and other immune cells to release chemokines such as interleukin 8 (IL‐8) and damaged endothelial cells to release interleukin 33 (IL‐33). IL‐33 and IL‐8, along with other chemokines, create a gradient that guides the local infiltration of neutrophils; Neutrophils entering the injury site break through the barrier of the necrotic zone by using matrix metalloproteinases (MMPs) to clear cellular debris; (2) An appropriate concentration of IL‐8 can promote the recruitment of a large number of N2‐polarized neutrophils to the defect area. N2 neutrophils secrete angiogenic factors such as vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP9), fibroblast growth factor 2 (FGF2), among others. FGF2 stimulates endothelial cells to produce MMPs, promoting the migration of endothelial cells and perivascular cells, rebuilding the damaged vascular network. (3) Additionally, N2 neutrophils can release stromal cell‐derived factor 1 (SDF‐1) to recruit bone marrow mesenchymal stem cells (BMSCs) to participate in tissue repair and regeneration; (4) Neutrophils, as short‐lived cells, exhibit post‐repair fates such as necrosis, NETosis, apoptosis, and reverse migration. The neutrophil fate has a significant impact on the outcome of tissue repair. Among them, neutrophils undergoing reverse migration re‐enter the vascular system, pass through the lungs, and return to the bone marrow, where they are cleared; this process is considered the most favorable outcome for tissue repair. This figure was created using BioRender.com.

FIGURE 2

The process of neutrophil recruitment. First, neutrophils are released from the bone marrow, while endothelial cells upregulate selectins (E‐selectin) and integrin ligands (e.g., intercellular adhesion molecule 1 (ICAM‐1)). Subsequently, free neutrophils exhibit high expression of adhesion‐related proteins, including the E‐selectin receptor–ESL‐1, the chemokine receptor CXCL8R, and LFA‐1. These proteins facilitate the adherence and crawling of neutrophils on endothelial tissues via receptor‐ligand interactions. Ultimately, neutrophils transmigrate through the endothelial barrier to reach the damaged region. In cases where selectins or integrins are absent or mutated, neutrophil recruitment in organs such as the liver and lung can be mediated by Dipeptidase ‐ 1 (DPEP1). Specifically, in the inflamed liver, recruited neutrophils bypass the rolling phase and directly adhere to the injured area through the interaction between CD44 and hyaluronic acid (HA) on liver sinusoidal endothelial cells. This figure was created using BioRender.com.

FIGURE 3

The role of neutrophils in different tissue repair. Skin: Neutrophils release VEGF or (MMPs) to stimulate angiogenesis and cell proliferation, while also secreting relevant cytokines that promote macrophage M2 polarization, thereby promoting granulation tissue formation and laying the foundation for fibroblast deposition of collagen to strengthen regenerative tissue. Muscle: Neutrophils can directly promote cardiomyocyte proliferation via interleukin‐6 (IL‐6) and the downstream signal transducer and activator of transcription 3 (STAT3) pathway. Additionally, they can mediate M2‐type differentiation of macrophages through neutrophil gelatinase‐associated lipocalin (NGAL), leading to the secretion of oncostatin M (OSM) and the establishment of a positive feedback loop, which in turn facilitates muscle growth and repair following injury. Fracture: A large number of neutrophils, linked to fibrinogen binding, are found in fracture hematoma. These neutrophils promote early healing by producing “an emergency extracellular matrix.” N2‐neutrophils release stromal cell‐derived factor‐1 (SDF‐1), recruiting bone marrow mesenchymal stem cells (BMSCs) for bone repair and regeneration. Liver: Neutrophils promote M2‐type macrophage differentiation via ROS, enhancing liver repair; and support repair by producing MMP8 and MMP9 which can resolve fibrosis. After liver injury, leukemia suppressor factor receptor (LIFR) mediates neutrophil recruitment and activation. Neutrophils then secrete hepatocyte growth factor (HGF) to accelerate liver regeneration. This figure was created using BioRender.com.

FIGURE 4

Fate of neutrophils and the subsequent impact on tissue repair. The modes of neutrophil death include nonlytic PCD (apoptosis and autophagy), lytic PCD (necroptosis and pyroptosis), NETosis, and reverse migration. Neutrophil apoptosis signals “find me” and “eat me,” leading to macrophage clearance via efferocytosis and promoting a CD11^blow proresolution macrophage subset. Autophagy is triggered by pattern‐recognition receptors, forming intracellular vesicles and degrading cellular components. Necroptosis depends on receptor‐interacting protein kinase‐3 (RIPK3) and mixed lineage kinase domain‐like protein (MLKL), releasing damage‐associated molecular patterns (DAMPs) that exacerbate tissue injury, with products phagocytosed by macrophages. Pyroptosis requires Gasdermin D (GSDMD) and caspase‐1, while Gasdermin E (GSDME) loss specifically inhibits pyroptosis of neutrophils. DAMPs, pathogen‐associated molecular patterns (PAMPs), and bacterial can induce NETosis, where neutrophil extracellular traps (NETs) promote blood clotting and early tissue repair. CXCL1, myeloid‐derived growth factor (MYDGF), and CXCR4 drive reverse migration, reducing N1‐neutrophils, resolving inflammation, and supporting tissue regeneration. This figure was created using BioRender.com.