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Review
. 2018 Mar 20:5:43.
doi: 10.3389/fmed.2018.00043. eCollection 2018.

The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis

Omkar Desai  1 , Julia Winkler  1 , Maksym Minasyan  1 , Erica L Herzog  1
Affiliations
Review

The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis

Omkar Desai et al. Front Med (Lausanne). .

Abstract

The contribution of the immune system to idiopathic pulmonary fibrosis (IPF) remains poorly understood. While most sources agree that IPF does not result from a primary immunopathogenic mechanism, evidence gleaned from animal modeling and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. This review will synthesize the available data regarding the complex role of professional immune cells in IPF. The role of innate immune populations such as monocytes, macrophages, myeloid suppressor cells, and innate lymphoid cells will be discussed, as will the activation of these cells via pathogen-associated molecular patterns derived from invading or commensural microbes, and danger-associated molecular patterns derived from injured cells and tissues. The contribution of adaptive immune responses driven by T-helper cells and B cells will be reviewed as well. Each form of immune activation will be discussed in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area.

Keywords: adaptive immunity; fibroproliferation; innate immunity; lymphocyte; macrophage.

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Figures

Figure 1
Figure 1
Changing paradigms regarding the proposed pathogenesis of idiopathic pulmonary fibrosis (IPF). The left column presents previous concepts of IPF. In this setting, an initial stimulus affects the alveolar epithelium (blue and pale pink shapes). As shown in the middle panel on the left, this process results in the generation of apoptotic epithelial cells (light blue) and the recruitment and activation of various immune cells including various populations of macrophages (blue) and lymphocytes (green) that produce cytokines and chemokines (yellow). As shown in the third panel on the left, these inflammatory cells and substances induce the activation of fibroblasts (red) and myofibroblasts (orange) to result in TGFβ1 activation (small light green circles) and the deposition of excessively stiff and biochemically abnormal extracellular matrix (ECM, red crosshatched lines). Observations gleaned from clinical trials and experimental modeling have refined this paradigm, however, to result in the scheme shown on the right. In this newer model, the stimuli affecting the lung epithelium leads to fibroblast activation and ECM accumulation that can occur without a primary immunopathogenic component (second panel on left). Once the fibrotic response is established, resident and recruited immune cells, such as macrophages and lymphocytes, modulate existing responses through a variety of mechanisms.
Figure 2
Figure 2
Potential role of innate immunity in pulmonary fibrosis. In response to interactions with pathogen-associated molecular patterns or danger-associated molecular patterns, or to stimulation with various mediators, macrophages—both alveolar (aqua irregular shape) and interstitial (red irregular shape)—can adopt fibrosis modifying properties. These functions include production of TGFβ1, production of soluble mediators that cause fibroblast accumulation and activation, production of TIMPS and MMPS that participate in extracellular matrix (ECM) remodeling, production of angiogenic factors, secretion of lipid mediators, regulation of structural cell injury and stem cell renewal, and surfactant recycling. Neutrophils (purple polymorphonuclear circle) produce neutrophil elastase (NE), TIMPS, and MMPs that dictate whether ECM accumulates or is degraded. Neutrophils also participate in the formation of neutrophil extracellular traps, which may promote fibrosis via the production of TGFβ1 and subsequent myofibroblast activation. Circulating fibrocytes (orange spindle shaped cells) are bone marrow-derived mesenchymal cells that enter the lung via the vasculature. Once in the lung they adopt multiple functions that would be expected to modulate fibrogenesis including the ability to differentiate into fibroblasts and myofibroblasts, production of ECM, contraction of wounds, participate in antigen presentation, production of chemokines and cytokines, and regulation of angiogenesis via production of soluble mediators. Myeloid-derived suppressor cells (MDSC, blue) are immunosuppressive cells that show an association with ECM remodeling and pulmonary hypertension. Innate lymphoid cells (ILCs) produce cytokines that may regulate fibroblast accumulation and ECM production. In the above figure, the functions of each cell are depicted in font matching the cell’s color. Note that cells are not drawn to scale.
Figure 3
Figure 3
Putative role of adaptive immunity in idiopathic pulmonary fibrosis. Th1 (grey) cells may suppress fibroblast responses through the secretion of pro-inflammatory cytokines, such as interferon gamma and TNFα. Th2 (pink) and Th17 (green) cells stimulate fibroblast proliferation, activation, and extracellular matrix (ECM) production through their secretion of IL-4 and IL-13 (Th2) and IL-17 (Th17). Tregs (purple) may either promote fibrosis through production of PDGFβ and TGFβ1, or suppress fibrosis via poorly understood effects on fibrocyte accumulation. Note that image is not drawn to scale.
Figure 4
Figure 4
Unifying schematic of immunopathogenic mechanisms of idiopathic pulmonary fibrosis (IPF) reveals that many important fibrosis-promoting processes may be regulated by input from both the innate and adaptive immune systems. Currently available data suggest that innate mechanisms may dominate. For example, both alveolar and interstitial macrophages respond to innate immune ligands present in pathogen-associated molecular patterns or danger-associated molecular patterns to assume adopt fibrosis modifying properties, including production of TGFβ1, paracrine regulation of fibroblast accumulation and activation, production of TIMPS and MMPS that participate in extracellular matrix (ECM) remodeling, production of angiogenic factors, secretion of lipid mediators, regulation of structural cell injury and stem cell renewal, and surfactant recycling. Macrophages might also suppress fibrosis by stimulating a regenerative program in epithelial stem cells, by regulating MMPs and TIMPS, and by directly degrading collagen and ECM. Neutrophils may promote fibrosis via the formation of neutrophil extracellular traps (NETs), which may promote fibrosis via the production of TGFβ1 and subsequent myofibroblast activation. However, neutrophils may also suppress fibrosis by regulating the MMP:TIMP balance and producing neutrophil elastase (NE) which degrades ECM. Circulating fibrocytes possess several fibromodulatory, including the ability to differentiate into fibroblasts and myofibroblasts, production of ECM, contraction of wounds, participate in antigen presentation, production of chemokines and cytokines, and regulation of angiogenesis via production of soluble mediators. Myeloid-derived suppressor cells (blue) display show an association with ECM remodeling and pulmonary hypertension. Innate lymphoid cells (ILCs) produce cytokines that may regulate fibroblast accumulation and ECM production. In terms of the adaptive immune response, Th1 cells may suppress fibroblast responses through the secretion of pro-inflammatory cytokines while Th2 and Th17 cells stimulate fibroblast proliferation, activation, and ECM production. Tregs either promote fibrosis through production of PDGFβ and TGFβ1, or suppress fibrosis via poorly understood effects on fibrocyte accumulation. B cells are not shown in this figure given the largely speculative nature of their role in IPF. The redundancy and opposing effects of these functions likely accounts for the failure of IPF to respond to classical forms of immunosuppression. Given the pronounced contribution of the innate immune system, interventions targeting the recognition of, or response to, innate immune ligands might be of benefit.
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