PMC:7456455 / 8914-14147 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7456455","sourcedb":"PMC","sourceid":"7456455","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7456455","text":"3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying 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