Long known for hunting down microbial invaders inside our body, neutrophils are now being recognised for an unexpected role under our skin: as builders, not just foot soldiers.
“For decades, scientists thought the body had two separate defences: a physical barrier formed by structural cells to block microbes from entering, and—when that barrier is breached—immune cells that detect and destroy those invaders,” said Immanuel Kwok, a Group Leader at the A*STAR Singapore Immunology Network (A*STAR SIgN). “However, our recent findings challenge this long-standing division by showing that these mechanisms aren’t mutually exclusive.”
Kwok referred to the latest results of an international research project that revealed neutrophils not only populate the skin, but also strengthen the extracellular matrix (ECM), which acts as the skin barrier’s scaffolding and communications network.
The project was spearheaded by A*STAR Graduate Scholar Jackson Li at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Spain, and expanded at A*STAR SIgN with Kwok, former Principal Investigator Lai Guan Ng and colleagues; as well as partnering institutes in Spain, Germany, the US and China.
“Combining genetic, imaging and functional studies, we discovered that neutrophils not only fight infections after they occur, but also pre-emptively reinforce the body’s barriers against invasion,” said Kwok. “We confirmed this by showing that skin neutrophils produce ECM proteins, such as collagen, which are key structural components typically made by skin fibroblasts.”
Using mouse models, the team showed that skin neutrophils can be critical for maintaining the skin’s structural integrity. Mice that lacked neutrophils developed softer and more permeable skin, laden with thinner and weaker collagen fibres.
“Through imaging studies, we also observed that neutrophils continually remodel the ECM, forming protective collagen ‘rings’ around wounds to help block foreign molecules and bacteria,” Kwok added.
The team then tracked down and identified a molecular signalling pathway, TGFβ, as the key driver of ECM production by skin neutrophils. In mice with neutrophil-specific defects in TGFβ signalling, collagen levels were significantly lower than in healthy controls, leading to similar skin weakness as seen in mice without neutrophils.
“Neutrophils also seem to regulate the circadian dynamics of skin structure and barrier function,” said Kwok. “Skin normally varies in tensile stiffness through the day and night, but these diurnal fluctuations vanished when neutrophils were absent.”
Kwok added that these findings could help reshape strategies for wound healing and infection control. Correcting neutrophil function might accelerate skin repair in patients with chronic wounds or tackle the root causes of some infections, while TGFβ signalling could also be a potential therapeutic target for boosting skin barrier resilience.
“This groundbreaking discovery broadens our understanding of innate immunity and highlights the remarkable versatility of neutrophils in maintaining health,” said Kwok.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Singapore Immunology Network (A*STAR SIgN).
