Highlights

People who grow up and reside in different countries typically end up developing different cultures and habits. The same could be said of immune cells in the body, which reside in different tissue ‘niches’.

Led by Florent Ginhoux of A*STAR's Singapore Immunology Network (SIgN), a team of scientists has discovered two distinct groups of interstitial macrophages (a type of white blood cell) that coexist and occupy specific compartments of tissues in the body.

“Macrophages are immune cells implicated in maintaining the normal functioning of tissues, from neuronal activity in the brain to the clearance of dying cells in all tissues,” Ginhoux explained, adding that macrophages differ in their properties and behavior depending on their location within tissue niches. His team thus sought to understand what those differences are and how those differences arise.

Using a technique called single-cell mRNA sequencing, the researchers observed that macrophages surrounding nerve bundles and those near blood vessels had different ‘signatures’, based on the genes they expressed and the proteins they displayed. Macrophages associated with blood vessels were characterized as Lyve1^hiMHCII^lo, while those in close proximity to nerve bundles were characterized as Lyve1^loMHCII^hi.

The researchers further demonstrated that Lyve1^hiMHCII^lo macrophages were critical for maintaining blood vessel integrity, suppressing inflammation and reducing the extent to which collagen fibers are deposited in tissue. In mice whose Lyve1^hiMHCII^lo macrophages had been removed, the team recorded increased blood vessel leakiness and worsened inflammation which delayed healing in the heart and lungs, ultimately resulting in greater scarring of the tissue.

On the other hand, Lyve1^loMHCII^hi macrophages were more prone to interact with another subset of immune cells known as CD4⁺ T cells. Upon activation by the Lyve1^loMHCII^hi macrophages, the CD4⁺ T cells increase in number and turn into regulatory T cells (T_regs), which are known to play a role in preventing autoimmune reactions.

Importantly, Ginhoux’s team found that both Lyve1^hiMHCII^lo and Lyve1^loMHCII^hi macrophages have a common origin—both are derived from immature cells called blood monocytes. “This in turn implies that the tissue microenvironment—either the blood vessels or nerve fibers—is the driver of monocyte-specific differentiation into either Lyve1^hiMHCII^lo or Lyve1^loMHCII^hi macrophages,” said Ginhoux.

Since nerve bundles and blood vessels are common ‘sub-tissue niches’ in many parts of the body, the two distinct macrophage populations likely play important roles in health and disease. Ginhoux and colleagues thus intend to explore more deeply how the two types of macrophages contribute to the development of cancer, for instance.

“We are also trying to better understand the role of nerve bundle-associated Lyve1^loMHCII^hi macrophages. This subset of macrophages would be well placed to contribute to focal chemokine/cytokine gradients, which could promote tissue tolerance by modulating the activity of T_regs,” Ginhoux concluded.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).