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Review
. 2021 Apr 22:12:663203.
doi: 10.3389/fimmu.2021.663203. eCollection 2021.

Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?

Chiel van Geffen  1 , Astrid Deißler  1   2 , Markus Quante  2 , Harald Renz  3   4 , Dominik Hartl  5   6 , Saeed Kolahian  1   3   4
Affiliations
Review

Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?

Chiel van Geffen et al. Front Immunol. .

Abstract

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.

Keywords: idiopathic pulmonary fibrosis; macrophages; mesenchymal stem/stromal cells; myeloid-derived suppressor cells; pharmacotherapy; regulatory B cells; regulatory T cells; transplantation.

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Conflict of interest statement

Author DH was employed by the company Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Direct effects of regulatory immune cells on (myo)fibroblasts and extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF). Repeated tissue injury triggering chronic tissue damage resulting in inflammation, epithelial mesenchymal transition (EMT) and ultimately in excessive production and buildup of ECM by fibrocytes and (myo)fibroblasts (fibrosis) in the lungs, represents the main paradigm involved in the pathology of IPF. Immune cells with regulatory functions modulate (myo)fibroblast generation, (myo)fibroblast function and ECM homeostasis through various signaling pathways, and known direct pathways are listed here. Mesenchymal stem/stromal cells (MSCs) promote (myo)fibroblasts through fibroblast growth factor (FGF), transforming growth factor (TGF)-β and interleukin (IL)-1β, while MSC-derived extracellular vesicles (MSC-ECV) and stanniocalcin (SC)-1 have opposite effects. MSCs are also prone to myofibroblastic transition. Tregs promote fibrogenesis through TGF-β, platelet-derived growth factor (PDGF)-B and IL-1β, while inhibiting the recruitment of fibrocytes by inhibition of the CXCL12/CXCR4 axis as well as FGF-9. Macrophages enhance fibrosis through TGF-β, PDGF, tumor necrosis factor (TNF)-α, fibronectin (FN) and inhibit fibroblasts via itaconate and peroxisome proliferator-activated receptor (PPAR) ligands. Myeloid-derived suppressor cells (MDSCs) and regulatory B cells (Bregs) have been suggested to activate lung fibroblasts, possibly through TGF-β. Bregs inhibit autoreactive immunoglobulins, which may deposit in lung tissue and promote inflammation and IPF. Dendritic cells (DCs) have been shown to produce pro-fibrotic TGF-β and IL-1β. Macrophages (Macs) as well as DCs break down the ECM via matrix metalloproteinases (MMPs), a process that is inhibited by tissue inhibitors of metalloproteinases (TIMPs) produced by other macrophage subtypes. Both Macs and DCs have been found to produce fibronectin (FN), another ECM component. Blue lines represent the direct effects of regulatory immune cells on (myo)fibroblasts and ECM in IPF. Dashed lines represent interactions that are not firmly established in IPF. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.
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