Dr. Jekyll or Mr. Hyde? White blood cells with a split personality: macrophages
Inflammation is the body’s response to injury or infection.
A swollen ankle after a sprain? An infected wound, with red and swollen edges? Or a burn, with pain that pulsates? Blood vessels dilate to promote the influx of immune cells to kill invading organisms, clear debris and repair tissue.
Normally this process is beneficial because it allows our body to protect against infection and repair an injury ... once the problem is dealt with, everything should return to normal in a few hours or days. However, in some situations, our defense system is unable to "finish the job" and continues to exist in a state of permanent activation. This is chronic inflammation.
The mechanisms that put an end to the inflammatory process are poorly understood but are potentially defective during chronic inflammation and may be hijacked by invaders to avoid our défenses. These endogenous anti-inflammatory mechanisms are the focus of the research team of Toby Lawrence.
"Sometimes, bacterial or viral infections or repeated tissue injury persist for several years. Our immune system has continued the fight, but in vain. This eventually causes important collateral damage, including cancer," says Toby Lawrence. "This state of chronic inflammation in effect creates an environment conducive to the development of malignant tumors: activated cells and their continued production of proinflammatory compounds promote the growth, of cancer cells and eventually malignant tumors. Our hypothesis is that the same mechanisms to halt the acute inflammatory response are hijacked by pathogens and cancer cells to evade attack by our immune system."
The macrophage: Doctor Jekyll and Mister Hyde
in inflammation and cancer
For Toby Lawrence, the macrophage is the heart inflammation and cancer.
The etymology of the word teaches us that this white blood cell, literally "big eater", engulfs cellular debris and pathogens present in the tissues that it infiltrates. In fact, macrophages are highly versatile cells, whose properties depend strongly on their tissue location and the pathological context in which they operate. Among the siblings in this heterogeneous family, there are at one extreme, "classical" macrophages (pro-inflammatory), potent killers of invading microbes or cancer cells and at the other, "alternative" macrophages present within tumors, which promote formation of blood vessels needed for tumor growth and metastasis and suppress anti-tumor immune responses.
Many clinical studies have also established a correlation between infiltration of tumors by these alternative macrophages and decreased patient survival.
This apparent contradiction - two potentially conflicting functions carried out by the same entity - represents in fact what may well happen to immune cells depending on the signals they receive and the partners with which they communicate.
At the heart of the control systems of the macrophage,
a molecular regulator of genes: NFkB
A small molecule called NFkB regulates cellular mechanisms involved in immune and inflammatory responses, particularly those that govern the multiple functions of macrophages.
"NFkB is a transcription factor, that is to say, a molecule that orchestrates activation of a large number of genes, dictating cell behavior in response to various stimuli (stress, UV radiation, inhaled particles, immunological signals ...). Like many other groups, we thought that NFkB was a tempting therapeutic target, since modulating its activity could potentially control many cellular events," says Toby Lawrence. "However, NFkB exists in and controls virtually all body cells, so the difficulty lies in the selection of cells in which it is manipulated. "
The team of Toby Lawrence has performed this manipulation successfully. While total inactivation of NFkB leads invariably to death of the mouse, its inactivation in macrophages alone can reveal their pro-tumor functions but also the role played by NFkB in these functions. Thus, in mice whose macrophages lack functional NFkB, tumors grow more slowly, because anti-tumor immune responses are more effective.
"Today, using this model we study networks of activation and interaction between different participating immune cells. We also use it as an adjunct to in vitro experiments to describe the mechanisms responsible for the plasticity of macrophages and possibly to identify regulatory pathways not controlled by NFkB," concludes Toby Lawrence.
By controlling these mechanisms, the team of Toby Lawrence may then make the most of the multiple properties of these cells to transform each macrophage into a kind Doctor Jekyll for the benefit of patients with cancer, infectious diseases or immunological disorders.