Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis

Abstract

The roles of macrophages in type 2-driven inflammation and fibrosis remain unclear. Here, using CD11b-Diphtheria Toxin Receptor (DTR) transgenic mice and three models of IL-13-dependent inflammation, fibrosis, and immunity, we show that CD11b+ F4/80+ Ly6C+ macrophages are required for the maintenance of type-2 immunity within affected tissues but not secondary lymphoid organs. Direct depletion of macrophages during the maintenance or resolution phases of secondary S. mansoni egg-induced granuloma formation caused a profound decrease in inflammation, fibrosis, and type-2 gene expression. Additional studies with CD11c-DTR and CD11b/CD11c-DTR double transgenic mice suggested that macrophages but not dendritic cells were critical. Mechanistically, macrophage depletion impaired effector CD4+ Th2 cell homing and activation within the inflamed lung. Depletion of CD11b+ F4/80+ Ly6C+ macrophages similarly reduced house dust mite-induced allergic lung inflammation and suppressed IL-13-dependent immunity to the nematode parasite Nippostrongylus brasiliensis. Consequently, therapeutic strategies targeting macrophages offer a novel approach to ameliorate established type-2 inflammatory diseases.

Macrophages in Tissue Repair, Regeneration, and Fibrosis

“…However, the contribution of macrophages to the development and maintenance of IL-13-dependent fibrosis is less clear as macrophages are not thought to be a major source of IL-13 (Wynn, 2004). To investigate the role of macrophages in a model of IL-13 driven fibrosis, Borthwick and colleagues have employed CD11b-DTR mice and depleted CD11b + monocytes and macrophages at different time points in three models of type-2 cytokine-driven disease (Borthwick et al, 2015). Here, monocyte and macrophage but not dendritic cell depletion during the maintenance and resolution phases caused a profound decrease in inflammation, fibrosis, and type 2 gene expression in the tissues but not in secondary lymphoid organs, suggesting that macrophages are critical to the maintenance of type 2 inflammation in the injured lung.…”

“…Related studies have also identified the chemokine receptor CCR8 as a major mediator of macrophage recruitment to injured liver, with CCL1-directed migration controlling the recruitment of classical inflammatory monocytes that promote TGF-β1-dependent fibrosis induced by CCL4 or bile duct ligation (Heymann et al, 2012). Thus, in addition to producing important pro-fibrotic mediators like TGF-β1 (Figure 2), monocytes and macrophages can also promote fibrosis indirectly by orchestrating local inflammatory reactions that maintain fibrotic responses or by blocking the emergence of pro-resolution pathways (Borthwick et al, 2015; Ehling et al, 2014; Mitchell et al, 2009). …”

Immune-mediated inflammation in the pathogenesis of emphysema: insights from mouse models

“…For example, M2-derived factors including Fizz1/Relmα and Arginase-1 have been shown to limit IL-13-dependent fibrotic repair processes such as collagen deposition, eosinophil infiltration, CD4 + T cell activation, and granuloma formation (Wynn, 2015). During a properly regulated response, these M2 cells can also receive additional signals from the local environment that transition them towards a phenotype capable of remodeling newly deposited extracellular matrix components through the production of tissue proteases (Borthwick, et al, 2016, Novak and Koh, 2013). It is possible that a dysregulation of these macrophage-coordinated repair mechanisms establishes a detrimental cycle that is the basis for the destructive lung pathology observed in progressive emphysema as illustrated in Figure 4.…”

Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis

“…Nevertheless, the mechanisms that govern tissue regeneration versus pathological type-2 cytokine-driven fibrosis remain unclear. While previous studies have implicated M2 macrophages in repair and fibrosis (Borthwick et al, 2015; Chen et al, 2012), other cells including hepatocytes, cholangiocytes, HPCs, and fibroblasts also express functional IL-4 and IL-13 receptors, yet their roles in the progression of liver disease, steatosis, fibrosis, DR, and liver regeneration during chronic type-2 cytokine-driven inflammatory responses have remained unclear. Moreover, while clinical studies have found elevated type-2 cytokines and receptor expression in human patients with biliary atresia (Li et al, 2011), primary biliary cirrhosis, primary sclerosing cholangitis, hepatitis C infection, and autoimmune hepatitis (Landi et al, 2014), no previous studies have directly investigated the causal relationships between type-2 cytokine-driven fibrosis and DR.…”