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Tissue-resident macrophages are important natural immune cells that are found in almost all tissues and organs of the body and play a role in host defense, inflammatory diseases , maintenance of immune homeostasis, and tissue repair. important role. Alveolar macrophages (AM) are tissue-resident macrophages that colonize the alveolar surface and are the most abundant immune cells on the alveolar surface (more than 95% in mice) , are the immune system The first line of defense against respiratory infections . AM develops from embryonic liver mononuclear cells , matures during the neonatal period, and can maintain self-renewal throughout life.
Resident AMs derived from embryonic monocytes are critical for defense against respiratory viral infections. Resident AMs of embryonic origin have been found to be replaced by peripheral monocyte-derived AMs in patients and mouse models of various respiratory infections. However, the kinetics of cellular replacement and the long-term consequences of this replacement in subsequent respiratory viral infections are unclear.
On July 1, 2022, the Manfred Kopf team at the Swiss Federal Institute of Technology in Zurich (ETH Zurich) published an article on Sci ImmunolMonocyte-derived alveolar macrophages autonomously determine severe outcome of respiratory viral infection . Use several different small The mouse model, accurately demonstrates the substitution kinetics, phenotypic characteristics, gene expression characteristics, metabolic characteristics and functions of AMs of different origins after respiratory virus infection.
The authors found that influenza virus infection of can induce a sharp decrease in the number of resident AMs in mice, and AMs can be quickly replenished through self-renewal within 2 weeks. Two populations of AMs distinguished by Siglec-F molecules were shown in the alveoli 5 weeks after infection. Embryonic-derived resident AM (FeMo-AM) expresses high levels of Siglec-F, whereas peripheral monocyte-derived AM (BMo-AM) expresses lower levels of Siglec-F. BMo-AM exhibits higher glycolytic levels and proliferation ability, thereby gradually replacing FeMo-AM. In order to directly compare the functions of BMo-AM and FeMo-AM in respiratory virus infection, the authors separately transferred BMo-AM and FeMo-AM into AM-deficient neonatal mice to reconstruct their AM, and found that BMo-AM-transfected mice It is more susceptible to influenza virus and produces more severe cytokine storm and death. Similar to infected individuals, BMo-AM gradually replaces FeMo-AM with age. The gradual accumulation of BMo-AM makes elderly individuals more susceptible to respiratory viruses and more likely to produce a cytokine storm effect.
In addition, it is generally believed in tissue macrophage research that the tissue microenvironment is the main factor leading to differences in macrophage function. In this study, the authors compared two groups of alveolar macrophages in the same microenvironment and found that the source of alveolar macrophages is also a significant factor determining their phenotype, gene expression profile and function.
In conclusion, this study reveals that peripheral monocyte-derived AM induces a more severe cytokine storm (Nature over nurture) in respiratory viral infections than resident AM, explaining the recurrent lung infections and the higher incidence of respiratory viral infections in elderly individuals. as a serious mechanism and provides a possible intervention method for cytokine storm caused by respiratory viral infection.
Figure 1. Peripheral monocyte-derived alveolar macrophages continue to replace resident alveolar macrophages, explaining the mechanism of recurrent lung infections and severe respiratory viral infections in elderly individuals.
Professor ETH Zurich Manfred Kopf contributed to this article Corresponding author . Dr. Li Fengqi and Dr. Federica Piattini from ETH Zurich are the first authors of this article.
It is worth mentioning that this study is the third masterpiece in a series of work conducted by Dr. Li Fengqi and his supervisor Professor Manfred Kopf in the field of alveolar macrophages. Previously, the author published a paper in EMBO J (2020) describing the alveolar macrophages. The mechanism by which macrophages originate from embryonic monocytes (PMID: 31894879). Subsequently, in April 2022, the author published an article (PMID: 35393945) in JCI Insight. Through in vitro culture, long-term stable proliferation of alveolar macrophages was obtained, and a complete system for in vitro genetic modification and in vivo macrophage treatment was established. , successfully treated pulmonary alveolar proteinosis (a rare disease) in mice, opening up new possibilities for immune cell therapy of lung diseases (Figure 2) .
Figure 2. Alveolar macrophage in vitro culture, genetic modification and in vivo cell therapy route
Dr. Li Fengqi has established his own research group in China and continues to engage in mechanism research and translational research on respiratory diseases. His research group is currently looking for interested research assistants, postdoctoral fellows and graduate students. Candidates with a background in immunology or bioinformatics will be given priority.
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