Further comments on the role of ACE‐2 positive macrophages in human lung

Abstract

The ACE2 expression on the surface of macrophages have been wellestablished by studies such as ACE2 on alveolar macrophages [2-6], blood monocyte-derived macrophages [7][8][9], and macrophages of atherosclerotic carotid arteries [10]. Specifically, the ACE2 protein expression on alveolar macrophages has been demonstrated by different studies with lung tissues from normal human and COVID-19 patients (Table 1). Recently, Wang et al. demonstrated that alveolar macrophages derived from COVID-19 patients displayed ACE2 receptor, which can be infected by . Furthermore, there was high ACE2 expression on normal lung macrophages that enables binding to the S protein [4]. Taken together, these publications support the conclusion and hypothesis regarding the action of alveolar macrophages in the pathogenesis of [17][18][19].There were inconsistent results regarding the ACE2 mRNA expression in alveolar macrophages reported by RNA-seq analysis.Contrasted with the reports [14-16], the ACE2 mRNA expression in alveolar macrophages were indicated by other groups [5,11,13].In agreement with these studies, our current studies have demonstrated ACE2 protein expression on alveolar, lipopolysaccharide (LPS)treated and other tissue macrophages [1]. These findings are consistent with other reports [2,[4][5][6][7]. For alveolar macrophages, there are different subpopulations with different phenotypes [20,21]. To isolate macrophages, all procedures need to be performed on ice with cold phosphate buffered saline (PBS) to avoid the adherence of macrophages to vessels. Therefore, some macrophages may be potentially lost during the cDNA library preparations for bulk or single cell RNAseq. The transcriptomic data from bulk or single cell RNA-seq requires further validation due to the poor correlation between transcriptomic analysis and protein abundance [22]. Hikmet et al. performed a body-wide analysis of ACE2 expressionat the protein level [12] by using Lab Vision Autostainer 480S Module (Thermo Fisher Scientific, Freemont, CA). The analysis failed to identify ACE2 expressions in lung macrophages. These inconsistent results were potentially due to the procedure of antigen retrieval, which was essential to unmask the low-level or formalin cross-linked tissue antigens in formalin-fixed paraffin-embedded tissues, Antigens were normally retrieved using a pressure cooker and the citrate-based Antigen Unmasking Solution pH 6.0 Vector Laboratories,

SARS-CoV-2 infection of phagocytic immune cells and COVID-19 pathology: Antibody-dependent as well as independent cell entry

“…While it was discovered that there is little to no expression of ACE-2 on most human peripheral blood immune cells it was also found that ACE-2 is highly expressed on tissue macrophages ( 21 , 22 ) including alveolar macrophages, and macrophages of arteries ( 21 , 23 ).…”

Modulations of Homeostatic ACE2, CD147, GRP78 Pathways Correlate with Vascular and Endothelial Performance Markers during Pulmonary SARS-CoV-2 Infection

“…Macrophages and myeloid lineage cells are not the primary targets of SARS-CoV-2 infection. However, ACE2 expression on alveolar and blood-derived macrophages is well established in patients during SARS-CoV-2 infection [ 58 , 59 ]. As shown in a recently established system comprising primary and cultured macrophages, expression of ACE2 supports productive viral infection and proinflammatory cytokine responses that may shape the outcome of infection [ 18 ].…”

Type 2 Immunity and Its Impact on COVID-19 Infection in the Airways

“…This process may help virus clearance and further spread. In contrast, some other studies have demonstrated a higher level of ACE2 expression in primary human alveolar macrophages and suggest that alveolar macrophages can be directly targeted by SARS-CoV-2 virus [ 52 , 53 ]. However, a lower level of ACE2 expression is reported in M2 alveolar macrophages compared to M1 [ 52 ].…”

“…In contrast, some other studies have demonstrated a higher level of ACE2 expression in primary human alveolar macrophages and suggest that alveolar macrophages can be directly targeted by SARS-CoV-2 virus [ 52 , 53 ]. However, a lower level of ACE2 expression is reported in M2 alveolar macrophages compared to M1 [ 52 ]. Therefore, phenotypic skewing of alveolar macrophages towards M2 may reduce the self-susceptibility to the virus due to its lower ACE2 expression and also may protect epithelial cells from virus through efficient phagocytosis.…”