Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2

Abstract

Monocytes undergo phenotypic and functional changes in response to inflammatory cues, but the molecular signals that drive different monocyte states remain largely undefined. We show that monocytes acquire macrophage markers upon glomerulonephritis and may be derived from CCR2+CX3CR1+ double-positive monocytes, which are preferentially recruited, dwell within glomerular capillaries, and acquire proinflammatory characteristics in the nephritic kidney. Mechanistically, the transition to immature macrophages begins within the vasculature and relies on CCR2 in circulating cells and TNFR2 in parenchymal cells, findings that are recapitulated in vitro with monocytes cocultured with TNF-TNFR2–activated endothelial cells generating CCR2 ligands. Single-cell RNA sequencing of cocultures defines a CCR2-dependent monocyte differentiation path associated with the acquisition of immune effector functions and generation of CCR2 ligands. Immature macrophages are detected in the urine of lupus nephritis patients, and their frequency correlates with clinical disease. In conclusion, CCR2-dependent functional specialization of monocytes into macrophages begins within the TNF-TNFR2–activated vasculature and may establish a CCR2-based autocrine, feed-forward loop that amplifies renal inflammation.

Single-cell sequencing of PBMC characterizes the altered transcriptomic landscape of classical monocytes in BNT162b2-induced myocarditis

“…An essential role of monocytes is to sense the environment and differentiate into macrophages in tissues, which proliferate upon inflammatory stimuli in the bone marrow ( 6 ) and their phenotypic and functional profiles change upon inflammatory signals and hence are important in disease progression ( 7 ). In cardiovascular diseases, an increased number of circulating monocytes is observed in patients with acute myocardial infarction ( 8 , 9 ).…”

Role of endothelial cells in graft-versus-host disease

“…EPCs express TNF receptor II (TNFRII) on their surface that binds to TNFα and exerts an immunosuppressive effect on T cells in part by secretion of anti-inflammatory TGFβ, IL-10 and HLA-G cytokines ( 55 ). Additionally, TNF-TNFRII activated endothelial cells produce CCR2 ligands, that can in turn promote the differentiation of CCR2+ monocytes into immature macrophages that can promote inflammation ( 56 ).…”

Tumor-specific CD4 T cells instruct monocyte differentiation in pancreatic ductal adenocarcinoma

“…Given the proposed role of TNFα in driving inflammatory macrophages in other models 54 and NicheNet (Figure 4E), we next assessed if loss of TNF receptor signaling impacted macrophage fate by implanting KPC 2a tumors into TNFR1 KO mice. Although we observed a minor trend for enrichment of MHCII hi macrophages, this was not significant, and the proportion and number of TAM subpopulations was largely similar at day 7 (Supplemental figure 10).…”