Monocyte Function Implicated in Immune System Efficacy

Successful cell division and proliferation is essential for the formation of complex organisms. When the proliferation of cells is no longer appropriately regulated, it can lead to the development of diseases, among which cancer represents the most striking example. However, researchers from the GIGA Institute at the University of Liège have discovered that, in a healthy individual, monocytes also have this proliferation ability.

The team discovered that blood monocytes can generate a pool of monocytes in the tissues, giving rise to macrophages, which protect us against microbes and support the proper functioning of our organs. This discovery changes our understanding of cell proliferation's role in immune system maintenance.

Thomas Marichal, senior author of the study, says that this is a significant discovery, suggesting that the information that can be drawn from an enumeration of blood monocytes, classically carried out during a blood test, would reflect only little of what is happening at the level of the tissues during infection or inflammation since monocytes can proliferate when they enter tissues. Fortunately, this proliferation is extremely well-controlled and does not lead to a tumoral process. It has only one goal: to allow, as effectively as possible, the replacement of immune cells that populate our tissues: the macrophages.

Resident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert essential tissue-supportive functions. The maintenance of RTMs is thought to rely either on differentiation from monocytes or RTM self-renewal.

For their work, the researchers used a mouse model of inducible lung interstitial macrophage (IM) niche depletion and refilling to investigate the development of IMs in vivo. Using time-course single-cell RNA-sequencing analyses, bone marrow chimeras, and gene targeting, the team found that engrafted Ly6C+ classical monocytes proliferated locally in a Csf1 receptor-dependent manner before differentiating into IMs.

Their data provide evidence that, in the mononuclear phagocyte system, the ability to proliferate is not merely restricted to myeloid progenitor cells and mature RTMs but is also a tightly regulated capability of monocytes developing into RTMs in vivo. The differentiation trajectories and the tissue cues are considered essential determinants of RTM identity and function.

While currently, the repopulation and maintenance of RTM niches are thought to be achieved either through monocyte engraftment and differentiation or through the self-renewal of mature RTMs, the slow turnover of RTMs at steady state and the lack of models that allow the capture of rare events, such as monocyte-to-RTM transitioning cells, have hampered investigations of RTM dynamics in vivo.

The study shows that monocytes play a critical role in maintaining the balance of the immune cells and supporting proper organ function. These findings have the potential to pave the way for new therapies that harness the ability of monocytes to proliferate and differentiate into immune cells, thereby helping patients with diseases that affect the immune system, such as autoimmune disorders or cancer.