Nanoparticle targeting of de novo profibrotic macrophages mitigates lung fibrosis

Abstract

Significance Current therapies for pulmonary fibrosis (PF) focus on slowing disease progression and reducing functional decline in patients by dampening the activation of fibroblasts and other implicated cells. There is a need for strategies that target the essential cells and signaling pathways involved in disease pathogenesis. Monocyte-derived macrophages (Mo-Macs) are known to express profibrotic genes and are involved in the pathogenesis of PF. Our results show that engineered mannosylated albumin nanoparticles specifically targeted disease-inducing Mo-Macs, and further, that nanoparticles efficiently delivered small-interfering RNA against profibrotic cytokine tumor growth factor β1 to prevent bleomycin-induced lung fibrosis.

The emerging roles of interstitial macrophages in pulmonary fibrosis: A perspective from scRNA-seq analyses

“…M2-polarized macrophages are associated with TGF-β expression and are involved in lung fibrosis via MMP-28 and MBD2 ( 82 , 83 ). Macrophage-produced TGF-β could promote lung fibrosis by inducing fibroblast differentiation ( 84 , 85 ). In addition, co-culture of SiglecF + CD11c + MHCII hi intermediate macrophages from a BLM-induced mouse model increased fibroblast proliferation through the secretion of Pdgf-aa ( 46 ).…”

“…Recent study found that resident AMs were replaced by a population of newly arrived monocyte-derived IMs during bleomycin-induced lung fibrosis. The transition macrophage is characterized as SiglecF + CD11b + and CD206 hi ( 85 ). Research on IPF patients also found that IMs could differentiate into AMs, and M2 macrophages were present in the early stages of fibrosis ( 70 ).…”

Salt-inducible kinase 2 regulates fibrosis during bleomycin-induced lung injury

“…A recent report suggests that peptides targeting CD206 are protective in bleomycin-induced fibrosis by promoting cell death in CD206 +ve macrophages ( 69 ). Nanoparticles targeting TGFβ siRNA to CD206 +ve macrophages can also reduce bleomycin-induced fibrosis ( 15 ). While these findings support a role for CD206 +ve macrophages, it does not address if CD206 is directly important in the response to bleomycin or if it only acts as a marker for alveolar macrophages that allows them to be targeted in vivo .…”

“…For example, depletion of macrophages with clodronate reduces bleomycin-induced lung fibrosis ( 8 , 13 ), whereas macrophage colony-stimulating factor 1 (M-CSF1) knockout mice (which have greatly reduced macrophage numbers) show a similar protection ( 14 ). More recently, it has been suggested that the differentiation of monocyte-derived alveolar macrophages, rather than pre-existing tissue resident alveolar macrophages, is required for bleomycin-induced fibrosis ( 15 , 16 ). Knockout of proteins that promote an M2/IL-4-like activation phenotype has been reported to protect against bleomycin-induced fibrosis and reduce expression of markers associated with IL-4-induced activation of macrophages in the lung ( 17 , 18 , 19 , 20 , 21 ).…”

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

“…Second, IPF is a highly complex disease, and multiple factors participate in its occurrence and progression. For instance, it is well documented that lung macrophages and its subpopulations play pivotal roles in pulmonary fibrosis pathogenesis ( 142 – 145 ). Recently, Hartley and colleagues investigated PD-L1 signaling in macrophages and the effects of PD-L1 antibody treatment on tumor-associated macrophages (TAM) responses ( 146 ).…”