Alveolar Epithelial Cells Promote IGF-1 Production by Alveolar Macrophages Through TGF-β to Suppress Endogenous Inflammatory Signals

Abstract

To maintain alveolar gas exchange, the alveolar surface has to limit unnecessary inflammatory responses. This involves crosstalk between alveolar epithelial cells (AECs) and alveolar macrophages (AMs) in response to damaging factors. We recently showed that insulin-like growth factor (IGF)-1 regulates the phagocytosis of AECs. AMs secrete IGF-1 into the bronchoalveolar lavage fluid (BALF) in response to inflammatory stimuli. However, whether AECs regulate the production of IGF-1 by AMs in response to inflammatory signals remains unclear, as well as the role of IGF-1 in controlling the alveolar balance in the crosstalk between AMs and AECs under inflammatory conditions. In this study, we demonstrated that IGF-1 was upregulated in BALF and lung tissues of acute lung injury (ALI) mice, and that the increased IGF-1 was mainly derived from AMs. In vitro experiments showed that the production and secretion of IGF-1 by AMs as well as the expression of TGF-β were increased in LPS-stimulated AEC-conditioned medium (AEC-CM). Pharmacological blocking of TGF-β in AECs and addition of TGF-β neutralizing antibody to AEC-CM suggested that this AEC-derived cytokine mediates the increased production and secretion of IGF-1 from AMs. Blocking TGF-β synthesis or treatment with TGF-β neutralizing antibody attenuated the increase of IGF-1 in BALF in ALI mice. TGF-β induced the production of IGF-1 by AMs through the PI3K/Akt signaling pathway. IGF-1 prevented LPS-induced p38 MAPK activation and the expression of the inflammatory factors MCP-1, TNF-α, and IL-1β in AECs. However, IGF-1 upregulated PPARγ to increase the phagocytosis of apoptotic cells by AECs. Intratracheal instillation of IGF-1 decreased the number of polymorphonuclear neutrophils in BALF of ALI model mice, reduced alveolar congestion and edema, and suppressed inflammatory cell infiltration in lung tissues. These results elucidated a mechanism by which AECs used TGF-β to regulate IGF-1 production from AMs to attenuate endogenous inflammatory signals during alveolar inflammation.

Genetically predicted high IGF-1 levels showed protective effects on COVID-19 susceptibility and hospitalization: a Mendelian randomisation study with data from 60 studies across 25 countries

“…This AM-derived IGF-1 attenuated the p38 mitogen-activated protein kinase inflammatory signal in AECs and promoted the phagocytosis of apoptotic cells by AECs. This two-way communication between AECs and AMs represents a well-tuned system for the regulation of the inflammatory response in alveoli ( Mu et al, 2020 ). Taken together, these studies provide biological evidence supporting that IGF-1 might be an important anti-inflammatory factor in the alveolar microenvironment and thus may contribute to improve COVID-19 outcomes.…”

Evaluation serum levels of Insulin Growth Factor-1 (IGF-1) and its association with clinical parameters in severe COVID-19

“…Furthermore, IGF-1 is involved in regulating the biological responses of the immune system through phosphatidylinositol-3-kinases/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) signaling pathways (Myers et al 1992 ). Various studies have proven the role of the IGF-1 signal transduction in lung development, as well as inflammatory diseases like ALI and Acute respiratory disease syndrome (ARDS), asthma, cancer, inflammation, and fibrosis (Stiles and D'Ercole 1990 ; Ahasic et al 2012 ; Mu et al 2020 ; Narasaraju et al 2006 ; He et al 2019 ; Li et al 2016 ). IGF-1 is also implicated in the regulation of inflammation in the immune system (DeBoer et al 2017 ; Heemskerk et al 1999 ).…”

Macrophage Sprouty4 deficiency diminishes sepsis-induced acute lung injury in mice

“…Various studies have shown that crosstalk between AECs and macrophages is essential to maintain lung homeostasis [ [51] , [52] , [53] ]. Mu et al found that AECs-derived transforming growth factor-β acted on macrophages to suppress endogenous inflammatory signals during ALI [ 54 ]. Meanwhile, exosomes-derived from AECs significantly promoted the activation of macrophages, thereby exacerbating pulmonary inflammation of ALI mice [ 55 ].…”