Covid-19: Innate Immune Cell Activation Causes Lung Fibrosis

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The COVID-19 pandemic has had a significant impact on global health, with millions of cases and deaths reported worldwide. While the majority of cases are mild, a significant proportion of patients develop severe disease, which can lead to respiratory failure and death.

One of the long-term complications of severe COVID-19 is lung fibrosis, which can cause permanent damage to the lungs and impair respiratory function. In this article, we will explore how COVID-19 innate immune cell activation can cause lung fibrosis and its implications for patient care.

The innate immune response is the body’s first line of defense against viral infections, including COVID-19. When the virus enters the body, immune cells such as macrophages, neutrophils, and dendritic cells are recruited to the site of infection. These cells release cytokines and chemokines that promote inflammation and recruit additional immune cells to the site of infection.

In some cases, the innate immune response can become dysregulated, leading to excessive inflammation and tissue damage. This dysregulated response can cause lung fibrosis, a condition in which excess connective tissue accumulates in the lungs, leading to scarring and impaired lung function.

Studies have shown that COVID-19 patients with severe disease have increased levels of proinflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in their lungs, which can contribute to the development of lung fibrosis.

In addition to the cytokine response, activated immune cells such as macrophages and fibroblasts have been shown to contribute to the development of fibrosis through the production of extracellular matrix proteins such as collagen. Fibrosis can also be caused by an imbalance of pro-fibrotic and anti-fibrotic factors, leading to excessive collagen deposition and scarring.

The development of lung fibrosis in COVID-19 patients has significant implications for patient care. Patients with lung fibrosis have reduced lung function, which can impair their ability to breathe and require supplemental oxygen. In severe cases, lung fibrosis can be life-threatening, leading to respiratory failure and death. Therefore, it is crucial to identify patients at risk of developing lung fibrosis and to develop effective treatments to prevent or slow the progression of fibrosis.

Currently, there is no specific treatment for lung fibrosis caused by COVID-19. However, treatments used in other fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), have shown promise in COVID-19 patients. For example, antifibrotic drugs such as pirfenidone and nintedanib have been used to slow the progression of lung fibrosis in IPF patients and are being evaluated in COVID-19 patients.

A new study by researchers from Stanford University School of Medicine has found the mechanism that may explain one of the most prevalent symptoms of Long COVID – breathing difficulties.

The research, published in the peer reviewed journal: Proceedings of the National Academy of Sciences, identifies the cause of fibrosis in the lungs as an overactivity of genes that control inflammation and immune responses.
https://www.pnas.org/doi/10.1073/pnas.2217199120

Exacerbated immune responses play a major role in the pathophysiology of SARS-CoV-2, leading to severe lung injury and respiratory failure (15).

In this study, by analyzing scRNA-seq data from severe COVID-19 lung tissues in comparison with a healthy cohort, we addressed the contribution of immune compartments and the important role of the profibrotic modulator JUN–CD47–IL-6 axis in promoting pulmonary fibrosis postacute COVID-19 infection.

We show that neutrophils and monocytes and macrophages are the most prevalent innate immune subsets present in these lungs and show a correlation with SARS-CoV-2–associated fibrotic progression, suggesting that these are the immediate effector cells responsible for the chronic inflammation in COVID lung fibrosis.

Several studies have reported that severe COVID-19 progression is associated with a dysregulated release of proinflammatory cytokines commonly called the “cytokine storm” (33).

Specifically, IL-6, TNF-α, vascular endothelial growth factor (VEGF), and IL-1α are enhanced in the bronchoalveolar lavage and plasma. Among these cytokines, IL-6 is thought to be required for pathogen recognition and subsequent translation into an emergency granulopoiesis response to inflammatory milieu.

Previous literature shows IL-6 signaling through the JanusKinase (JAK)–signal transducer and activator of transcription (STAT) pathway to stimulate neutrophil precursor proliferation and differentiation (34, 35). Also, our previous studies suggest IL-6 as an integral component in the initiation and progression of fibrosis via the JUN and CD47 axis (14).

Although previous scRNA-seq analyses of PBMCs failed to identify circulating cells producing IL-6 (15), our analysis concludes IL-6 to be produced by inflammatory cells as matured neutrophils and monocyte-derived alveolar macrophages (MoAM) in the lung tissue. Meanwhile, we identified that JUN and CD47 expression is up-regulated in SARS-CoV-2–infected lung tissues, especially in activated fibroblasts.

Mitigation of immune dysregulation is therefore viewed as a major therapeutic avenue for the treatment and prevention of COVID lung fibrosis. Inflammatory myeloid cells as neutrophil and macrophage are demonstrated that affect fibrosis progression accompanied by a dysregulation of the profibrotic modulating JUN–CD47–IL-6 axis.

Thereafter, we investigated the efficiency of combined CD47/IL-6 blockade for lung fibrosis in the COVID lung fibrosis mouse model and humanized COVID-19 mouse model. Overall, the robust improvement of fibrosis in a combinatorial therapy of CD47 and IL-6 inhibition highlights the importance of JUN, CD47, and IL-6 as potential therapeutic targets for resolving fibrosis in COVID lung fibrosis.

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