The last-minute redemption of inflammatory cells in lung repair
- 1Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
- 2Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias, Madrid, Spain
- 3Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
- 4Unidad de Cuidados Intensivos Cardiológicos, Hospital Universitario Central de Asturias, Oviedo, Spain
- Corresponding author: Guillermo M. Albaiceta (gma{at}crit-lab.org)
Abstract
Inflammatory cells play a key role in lung repair after acute injury. These cells switch to a pro-repair phenotype over time in response to extracellular signals. Among these, VEGF-C promotes neutrophil clearance (efferocytosis) in macrophages. https://bit.ly/3KixGnX
Inflammatory cells play a central role in the pathogenesis of acute lung injury. Danger signals within the alveolar structures trigger a stereotypical response that results in the activation of an inflammatory response within alveoli and the interstitium. In addition to resident cells, the release of proinflammatory mediators, including chemoattractants, results in the recruitment of inflammatory cells from the circulation. Activated macrophages and neutrophils participate in the early phase of acute injury, mainly by promoting tissue disruption [1]. This acute response aims to remove pathogens and damaged cells in an expedited way and, if the severity of injury is mild or moderate, may result in effective repair or even regeneration. However, in case of severe damage, the intra-alveolar inflammatory response may impair lung function, worsening gas exchange and respiratory mechanics.
Virtually all the pathogenetic mechanisms of severe acute lung injury are triggered by these inflammatory cells, including the release of proinflammatory cytokines, proteases and reactive oxygen species, that cause organ damage. By these reasons, prophylactic inhibition of the cell-mediated acute response has yielded beneficial results in almost all the experimental models tested [2, 3]. However, these findings contrast with the clinical evidence coming from patients with abnormal cell immunity, who often show worse outcomes than their control population [4]. This poor prognosis comes not only from the delayed clearance of the triggering event, but also from an impaired resolution and repair of the injured tissue, thus revealing a role of these cells in tissue repair [5].
Over the past years, the involvement of different neutrophil and monocyte/macrophage subclasses in regulation of the inflammatory response and lung repair has emerged, revealing a complex, cell-mediated mechanism to preserve and restore tissue homeostasis. In this issue of the European Respiratory Journal, Yamashita et al. [6] describe a novel mechanism of macrophage-mediated resolution of lung damage driven by activation of vascular endothelial growth factor (VEGF) type 3 receptors by VEGF-C. To put this new information in context, we will briefly review how macrophages and neutrophils orchestrate lung repair.
The lung at steady state contains alveolar (AM) and interstitial macrophages (IM). These populations may be augmented by monocyte-derived macrophages recruited from the circulation under inflammatory conditions. AMs are the main immune cell population present in the healthy lung. They are located in the luminal surface of the alveolar space and have a key role in maintaining pulmonary homeostasis, mainly by clearing cellular debris and excessive surfactant [7]. As the alveoli are constantly exposed to antigens, AMs must keep a suppressive phenotype in order to prevent overreaction. The alveolar epithelium promotes tolerance to innocuous antigens by both secretion of soluble factors like interleukin (IL)-10 [8] and cell–cell interactions [9]. Thus, AM responsiveness to a harmful antigen is strongly related to the integrity of the respiratory epithelium, as damage of the epithelium leads to lack of immunosuppressive signals and a shift towards a proinflammatory response by AMs. Therefore, AMs carry out an important gate-keeping role in the defence of the respiratory tract [10]. IMs, also referred as lung tissue macrophages, can be observed in multiple locations, from the bronchial interstitium, to the vicinity of lymphatic vessels and on the pleural surface [11]. These cells are considered a second line of defence against invading micro-organisms and have mainly an antigen-presenting and immunoregulatory activity [12]. Finally, monocyte-derived macrophages are recruited from the circulating pools in cases of severe injury and retain a more proinflammatory and profibrotic phenotype [13].
In acute inflammation, neutrophils are quickly recruited from the circulation into the airway space and play a dual role in the development and resolution of lung injury [14]. Mature neutrophils recruited at the sites of inflammation have a strong chemotactic and proinflammatory response. Even at this early phase, neutrophils may play pro-repair roles. Migration of neutrophils along the epithelium results in activation of the Wnt pathway, that triggers epithelial proliferation [15]. In addition, release of neutrophil extracellular traps (NETs) and anti-inflammatory lipidic mediators, such as lipoxin A4, contribute to mitigating the acute proinflammatory response. Neutrophils also phagocytose cell debris to provide a clean environment that facilitates repair [16].
It has recently been proposed that, rather than acting as different pre-defined cell subsets, the evolving nature of the inflammatory response induces a phenotypic switch in both macrophages and neutrophils from the proinflammatory roles previously described towards a pro-repair programme. Anti-inflammatory macrophages are induced by the exposure of AMs to transforming growth factor (TGF)-β or type II cytokines (IL-4 and IL-13) secreted by Th2 cells and type 2 innate lymphoid cells [17, 18]. One of the most important strategies carried on by these activated macrophages is efferocytosis, the phagocytosis of apoptotic cells (mainly neutrophils), which prevents the release of proinflammatory and toxic components to the environment [19]. This mechanism further induces macrophage reprogramming towards the secretion of anti-inflammatory cytokines (IL-10, TGF-β) and growth factors (including keratinocyte growth factor, VEGF variants, fibroblast growth factors 2 and 10 and insulin-like growth factor-1) that promote the proliferation of parenchymal cells [20, 21].
Similarly, extracellular signals such as TGF-β may polarise neutrophils towards a pro-repair phenotype characterised by the release of growth factors, including VEGF, and matrix metalloproteinases (MMPs) [22]. Several MMPs are essential for normal collagen deposition during the acute phase, and its subsequent digestion during repair [23]. This remodelled matrix facilitates epithelial migration and proliferation. Gelatinases (MMP-2 and MMP-9) have been involved in alveolar epithelial repair in several experimental models [24]. Furthermore, MMPs can cleave cyto- and chemokines, contributing to resolution of inflammation [25].
In this issue of the European Respiratory Journal, Yamashita et al. [6] add another piece of knowledge on the role of inflammatory cells in acute lung injury and repair. Using a smart combination of cell and animal models, the authors study the role of VEGF-C signalling in lung injury. During the acute phase, VEGF-C is involved in IL-10 secretion, thus contributing to attenuate inflammation, possibly by preserving the anti-inflammatory phenotype of resident cells. In a late phase, the study provides sound evidence on how VEGF-C signalling through VEGFR-3 receptor activates efferocytosis in AMs, contributing to tissue repair. Results using samples from patients with acute respiratory distress syndrome (ARDS) show a decreased activity of this pathway in monocyte-derived macrophages, reinforcing the translational nature of the study. These findings correlate with recent studies showing impaired efferocytosis in patients with ARDS [26].
The lipopolysaccharide model of lung injury results in a severe proinflammatory response that vanishes over time due to endogenous toxin clearance. Future studies should perform a careful dissection of these mechanisms in models with ongoing lung injury (i.e. with live pathogens), making a distinction among the existing macrophage subpopulations, and probably different patient endotypes, as up half of ARDS cases do not show a marked proinflammatory response to injury [27]. Despite these limitations, the beneficial effects observed suggest that, in contrast to the conflicting results observed with VEGFR1 and VEGFR2 stimulation [28], restoration of VEGF-C/VEGFR3 signalling could be a novel therapeutic target aimed to improve repair.
The article by Yamashita et al. [6] also highlights the complex crosstalk between the acute phase of injury and the subsequent repair. In the specific case of VEGF-C, its upregulation ameliorates early lung injury and promotes repair in a macrophage-mediated manner. Therefore, VEGF-C might qualify as a time-independent target. However, this is not always the case. Some molecules released during the acute phase cause tissue disruption, but are also required in later phases. As an example, TGF-β, which, as previously described, is a key regulator of the inflammatory cell reprogramming [18, 22] towards an anti-inflammatory, pro-repair phenotype (and also pro-fibrotic), facilitates lung oedema in the early phase [29]. Finally, other inflammatory mediators, such as IL-6, are released from macrophages and may decrease damage when released early [30, 31] but also be profibrotic during repair [32]. Collectively, these pleiotropic, time-dependent effects, make it difficult to identify viable therapeutic targets without considering their window of opportunity (figure 1). Indeed, targeting a specific cell population during the acute phase may have deleterious consequences for repair.
Therapeutic interventions aimed to repair a complex organ such as the lung will probably require multiple supportive and regenerative strategies over time. Identification of viable targets and timings is essential to later combine them in a therapeutic regime. Ultimately, hacking endogenous repair mechanisms that have been evolutionarily optimised without disturbing some steps of the process is a challenge that probably requires exogenous (bio)technological support to both foster endogenous rebuild and overcome the resulting side effects. The work by Yamashita et al. [6] provides sound evidence that VEGF-C can be part of these strategies.
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Footnotes
Conflict of interest: The authors have nothing to disclose.
Support statement: Supported by Instituto de Salud Carlos III (PI20/01360, FEDER funds). P. Martín-Vicente is the recipient of a grant from Instituto de Salud Carlos III (FI21/00168). C. López-Martínez is the recipient of a grant from Ministerio de Ciencia, Innovación y Universidades (FPU18/02965). Instituto Universitario de Oncología del Principado de Asturias is supported by Fundación Liberbank. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 23, 2021.
- Accepted January 10, 2022.
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