Older people often have a worse prognosis when they have viral infections in the lungs, such as the flu or COVID-19. Among the various factors that complicate the course of these infectious diseases is an uncontrolled inflammatory response, which harms patients by causing damage to lung tissue. Although immune cells called macrophages are known to be involved in this phenomenon, not all of the mechanisms involved are well understood.
Now, a team of researchers from the Federal Polytechnic University of Zurich has found a key element in mice that helps to understand why the elderly are particularly vulnerable to viral respiratory infections. The results of your workpublished in the journal Sciences Immunologyshow that the origin of macrophages in the lungs determines the severity of the disease.
Macrophages are cells that are part of the innate immune system and act early when pathogens and various foreign substances appear in the body. These white blood cells come from monocytes (immune cells that travel in the blood) when they leave the blood vessels and migrate to different tissues. Macrophages are responsible for devouring (phagocytizing) and destroying cellular debris as well as bacteria and viruses, which is why they are considered “cleaners” of cells. In addition, they also communicate with other defensive cells to warn of the presence of infectious agents by releasing messenger molecules (cytokines).
The new research found in mice that replacement of the normal population of macrophages residing in the alveoli (hemispherical cavities of the lungs where gas exchange occurs) with bone marrow-derived macrophages results in severe respiratory infection.
Under normal conditions, the macrophages that remain in the lungs of mice and humans come from fetal monocytes that have developed in the liver at the embryonic stage. These macrophages play a vital role in defending against viral infections. However, some infections such as those caused by influenza type A viruses can drastically reduce the number of macrophages (since they die in the defense process). Until the results of this research were published, it was not known where the new immune cells that repopulated the lungs came from and what consequences the death of a large proportion of macrophages in the lungs had on subsequent viral infections. Moreover, it was thought that the origin of alveolar macrophages did not influence their function.
Researchers have, however, verified that the origin of the aforementioned immune cells is essential in the response to viral respiratory infections, which belies the prevailing belief to date. To explore this question further, they used different mouse models as well as specific markers to identify macrophages derived from fetal monocytes and those from bone marrow. In turn, they also observed what happened to each population of macrophages after repeated infections with influenza A viruses or with the aging of the mice.
Initially, it was the lungs’ own macrophages that multiplied and restored the number of immune cells in the lungs after a viral infection. However, over the months, the macrophages from the bone marrow ended up “invading” the alveoli because they had a greater capacity to multiply. On the other hand, the “invading” macrophages triggered another inflammatory response, including a cytokine storm, which caused damage to the lungs. This change in macrophage populations, with a predominance of those from the bone marrow, also occurred gradually as the mice aged, even though they had never had the flu.
The consequence of the different origin of macrophages in the lungs was that the mice suffered from more severe influenza and died more. Indeed, when alveolar macrophages from old mice (which came from the bone marrow) were transplanted into young animals, the latter also suffered a worsening of the course of influenza, with a higher risk of death.
The authors explain that the results of their research are similar to those of other studies that have examined the lungs of people with severe COVID-19. Patients infected with SARS-CoV-2 with mild disease typically have an almost intact alveolar macrophage population, while those with severe infection have inflammatory macrophages originating from the bone marrow. The next step in this research is to find out what molecular mechanisms cause the death of macrophages residing in the alveoli.
Reference: “Monocyte-derived alveolar macrophages autonomously determine severe outcome of respiratory viral infection», Fengqi Li et al. Immunology, flight. 7, no. 73, July 1, 2022.