Illustration of a macrophage in pulmonary air sacs (alveoli)

Serious flu risk as immune cells change with age

Lung infections with the flu virus or a coronavirus more often lead to serious illness in the elderly. This is due to an excessive inflammatory response that causes damage to the lung tissue. The exact causes are not yet clear. Macrophages, also called the immune system’s scavenger cells, play a role. They release pro-inflammatory messengers, which then trigger a severe immune response.

A team of researchers led by Manfred Kopf, an immunologist and Professor of Molecular Biomedicine at ETH Zurich, has shown that scavenger cells native to the lung in mice — called embryonic alveolar macrophages — die quickly when the animals are infected with the influenza virus and become infected. replaced by bone marrow macrophages after a few days. The more severe the infection, the more embryonic alveolar macrophages die. The ETH immunologists recently reported their findings in the journal Science Immunology

Differences in function and disease progression

Macrophages have several functions, including the first line of defense against pathogens. In terms of developmental biology, they can be roughly divided into two groups. In humans and mice, all organs and tissues have resident, long-lasting macrophages that are already formed in the fetal liver during embryonic development and that perform specific functions in the different tissue types. The embryonic macrophages in the lungs are involved in the vital oxygen-carbon exchange that takes place in the alveoli.

The second group of macrophages arises during blood formation in the bone marrow and migrates through the bloodstream to various tissues, where they subsequently develop into tissue-specific macrophages.

“Until now, bone marrow-derived macrophages were thought to have the same function as alveolar macrophages originating in the fetal liver, and that this was true of all tissues,” explained Federica Piattini and Fengqi Li, who are part of the research group at cup. and both first authors of the paper. They have now disproved this hypothesis and show that in fact bone marrow-derived macrophages cause damage in cases of viral lung infection.

The two researchers created two groups of mice: one group had alveolar macrophages that emerged during the embryonic stage and the other group had bone marrow-derived macrophages. When infected with the influenza virus, the mice with the bone marrow-derived alveolar macrophages became much sicker and died. One reason for the severe disease course was that these macrophages caused a strong inflammatory response (cytokine storm).

The authors of the study conclude that the origin of macrophages plays a crucial role in the progression of the disease. And they showed that influenza infections in mice stimulate the replacement of alveolar macrophages.

Evidence of similar processes with Covid-19

According to the researchers, it is logical and valid to compare their flu experiments on mice with coronavirus infections in humans. “It seems that similar processes are taking place in the case of Covid-19,” Kopf says. A previous study reported that the embryonic pulmonary macrophages are largely preserved in Covid-19 patients with mild disease progression, while severe disease progression is associated with inflammatory alveolar macrophages that originate in the bone marrow.

However, it appeared that the embryonic alveolar macrophages were not replaced exclusively in severe viral infection. Kopf’s group showed that this replacement also occurs in aging mice, even if they had never been infected before. The transplantation of alveolar macrophages from old to young mice resulted in a severe flu progression that ended in death.

It is known that the elderly have a much higher risk of serious flu or Covid-19 infection. “There are certainly several reasons for this,” says Kopf. However, the new data suggest that the loss of embryonic macrophages over the course of life plays a role here.

The ETH professor and his team now plan to study the molecular mechanisms of dying embryonic alveolar macrophages.

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