COPD: The refuted macrophage dogma

22. April 2014

Therapy of many diseases is based on a theory, such as with COPD. Too bad if the theory is wrong. Scientists have been able to revoke a hypothesis of macrophages established decades ago and thereby for the first time enable the appropriate therapies.

For a long time there has dominated in immunology opinion the view that there are two types of macrophage: pro-inflammatory M1 and anti-inflammatory M2 macrophage. Macrophages as part of the innate immune system play an important role with many diseases and are present in all tissues in large numbers. It’s on the basis of this thesis that COPD patients, for example, are treated. It was postulated that the macrophage were responsible for the pro-inflammatory state and tried to suppress the reaction with anti-inflammatory medications. The desired successful outcome did not occur. The researchers and doctors could not explain it.

Faulty hypothesis – for decades

However, scientists working under Prof. Joachim L. Schultze of the Life & Medical Sciences (LIMES) Institute at the University of Bonn have now found and demonstrated that the initial hypothesis is false: namely, the dogma that there are only two types of macrophages.

In an extensive experiment the working group showed that macrophages respond to different stimuli using different programs. Prof. Schultze explains: “Macrophages probably work like a small computer. They get an input signal, for eg. a mixture of signal molecules, and then calculate a specific effector program, so that the situation in the tissue can be resolved optimally”. The scientists draw this hypothesis from the genome-wide analyses which they have done. Using 30 different stimuli they treated macrophages and on the basis of gene expression they measured which programs run their course in the macrophages. The measurements were then analysed impartially. “The data has spoken. There are not two kinds of macrophages, there are a whole lot of different ones”, explains Prof. Schultze. “This is also not surprising, because macrophages occur in all tissues and need to be able to adapt to a wide variety of bacteria, viruses and inflammatory responses rapidly and specifically”. The results have been published in the journal Immunity.

Path open for appropriate therapies

The findings from Bonn naturally complicate everything that had previously been regarded as self-evident and certain. As a result many colleagues sigh heavily when considering this sudden increase in complexity. Most, however, are relieved that the dogma is now disproved, as Prof. Schultze reports, because for many years there were research results that could not be explained using the previous theory. In addition, the way is now clear for new approaches in diagnosis and therapy of various diseases in which macrophages are involved.

COPD finally made treatable?

The Bonn scientists now want to deal intensively with COPD. In their analyses, they were able to show that macrophages have their completely own pattern in COPD patients. The “classical” markers with regard to this inflammatory response play no role. This also explains why the recent therapeutic approaches were ineffective: the medications have no effect on the active macrophages in COPD.

From transcriptome analyses the scientists are now able to deduce in different tissues which mechanisms belong to which macrophage characteristics. These can then be addressed therapeutically. New medications are sometimes not even necessary – the existing ones need only be used under the right medical conditions. An inflammation in the liver may therefore require a completely different treatment to an inflammation in the lungs or in the brain.

Different therapies over the course of the disease

Yet that’s not all. “Every disease at any time has its own profile”, explains Prof. Schultze. If in the case of a chronic disease the original initiator cannot be removed by the immune system, sometimes a reaction that makes the disease process more bearable for the body can be set in motion. This for example is the case when tissue becomes fibrotic. First, macrophages seek among other things to shut down the inflammatory ‘stove’. Failing that, macrophages can however move to another program and stimulate fibroblasts, which bring about its conversion into an inactive connective tissue.

Gold rush begins

The Bonn group has hardly been able to evade the requests for collaborative work. Pharmaceutical companies want to use the data obtained in the human system to benefit their own development projects, and researchers from various fields are asking for help in the evaluation of their own data.

Prof. Schultze and his team of experimentalists and bioinformaticians now want to focus on three thematic areas. One of those, as already mentioned, is COPD. Another one centres on arteriosclerosis, which is being studied in collaboration with Professor Latz. In the case of atherosclerosis as well there is evidence that the typical anti-inflammatory medications are not effective to the extent desired. The scientists have already found out in one collaborative project that there exists a central switch which is responsible for the reprogramming of the macrophages from meaningful activity cleansing cells in the blood vessels to pro-inflammatory activity. This switch is the protein ATF3. HDL brings about the effect via the switching of ATF3 that macrophages rediscover their original function and the inflammation comes to a halt. Further studies will show whether other molecules and active ingredients are also capable of doing the task. The third topical focus is macrophages in association with tumour events. Again here the existing doctrine until now led to the fact that the actually operating mechanisms had been overlooked. In a European cooperation network new insights should be gained here.

“It is good that the dogma has now fallen. It has hindered us from free thinking and in research. Now we can fullly look at the data in an unbiased manner and orient ourselves in relation to it”, Prof. Schultze says.

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