Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jul;22(3):141-160.
doi: 10.1038/s41435-021-00140-w. Epub 2021 Jun 17.

Role of DAMPs in respiratory virus-induced acute respiratory distress syndrome-with a preliminary reference to SARS-CoV-2 pneumonia

Walter Gottlieb Land  1   2
Affiliations
Review

Role of DAMPs in respiratory virus-induced acute respiratory distress syndrome-with a preliminary reference to SARS-CoV-2 pneumonia

Walter Gottlieb Land. Genes Immun. 2021 Jul.

Erratum in

Abstract

When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.

PubMed Disclaimer

Conflict of interest statement

The author declares no competing interests.

Figures

Fig. 1
Fig. 1. Schematic diagram of a conceptual model illustrating an injury-induced controlled homeostatic inflammatory response leading to restitutio ad integrum.
The initiating DAMP-promoted proinflammatory response proceeds—in near parallel—to a SAMP-promoted proresolving response. The short delay of the beginning of the proresolving response may be explained by the fact that SAMPs in terms of inducible suppressing DAMPs are secreted by DAMP-activated PRR-expressing cells. DAMPs damage-associated molecular patterns, MØ macrophages, nrp pro re nata, PRR pattern recognition molecule, Tregs T regulatory cells, Th1/17 cells T helper cells type 1/17. Note: Interaction of DAMPs with MAMPs in pathogen-triggered infectious inflammation not shown. Sources: This figure corresponds to Fig. 5.1 published in Ref. [11] (Section 5.2, p.152).
Fig. 2
Fig. 2. Schematic diagram of a conceptual model illustrating a severe/fatal injury-induced uncontrolled hyperinflammatory response. as observed in ARDS/SIRS/MOF.
The DAMP-induced hyperinflammatory response proceeds, in near parallel, to a long-lasting hyperresolution response (as observed, for example, in CARS) that is induced by production of counterbalancing SAMPs in excess (the controlled homeostatic proinflammatory and resolving responses are faded in, separated by dotted lines). The short delay of the begin of the hyperresolving response should symbolize that SAMPs in terms of inducible suppressing DAMPs are secreted by DAMP-activated PRR-expressing cells. The initial hyperinflammatory phase is associated with an increased risk of MOF, whereas the long-lasting hyperresolution phase is characterized by a state of immunosuppression that is associated with increased susceptibility of patients to infections. CARS compensatory antiinflammatory response syndrome, MOF multiple organ failure, PRR pattern recognition molecule, SIRS systemic inflammatory response syndrome. Sources: This figure is slightly modified from (1): Fig. 1 in Ref. [27]; (2) Fig. 8.1 in Ref. [11].
Fig. 3
Fig. 3. Simplified schematic diagram of a narrative model illustrating release of DAMPs from influenza virus-induced necroptotic cells.
Z-RNucleic acids produced by influenza viruses in the nucleus of infected cells (here symbolized by a lung epithelial cell) are sensed by host ZBP1, which activates RIPK3 and MLKL to lead to nuclear envelope rupture and necroptosis. Passive release of constitutive DAMPs, including nucleic acids, results in activation of PRR-bearing innate immune cells (here symbolized by an alveolar macrophage), which produce proinflammatory cytokines (including inducible DAMPs) and chemokines. This leads to subsequent recruitment of macrophages, neutrophils, and dendritic cells, which may be activated by inducible DAMPs to amplify the inflammatory response (not shown). cGas cyclic GMP-AMP synthase, dsRNA double-stranded RNA, HMGB1 high mobility group box 1, IFN interferon, MLKL mixed lineage kinucleic acidse domain-like protein, PRRs pattern recognition receptors, RHIM RIP homotypic interaction motif, RIG-I retinoic acid-inducible gene (protein) I, RIPK3 receptor-interacting serine/threonine-protein kinucleic acidse 3, ssRNA single-stranded RNA, Zα1/2 Z-form nucleic acid-binding domain1/2, TLR Toll-like receptor, TNF tumor necrosis factor, ZBP1 Z-DNA binding protein 1. Sources: [35, 44, 50].
Fig. 4
Fig. 4. Simplified schematic diagram of a conceptual model illustrating release of DAMPs from SARS-CoV/viroporin-induced pyroptotic cells.
The first priming step is exemplified by IFN receptor-triggered transcriptional pathways (NF-κB activation) to promote upregulation of NLRP3 and pro-IL-1β/pro-IL18 expression. The activation step is proposed to be triggered by SARS CoV viroporins via recruitment of NLRP3 to dTGN in the form of an early and common cellular event caused, for example, by virus-induced ER stress, ER stress-induced mitochondrial ROS production, calcium mobilization, and enhanced potassium efflux and (marked by purple arrows). Activated Gasdermin D-N then binds to lipids in the plasma membrane and forms large pores, leading to pyroptotic cell death and release of cellular contents such as DAMPs and matured IL-1β and IL-18. ASC apoptosis-associated speck-like protein containing a caspase recruitment domain, C C-terminal domain, CARD caspase-activating and recruiting domain, dTGN dispersed trans-Golgi network, eATP extracellular adenosine triphosphate, K+ potassium, NF-κB nuclear factor kappa B, IL interleukin, LRR leucine-rich repeats, N N-terminal domain, NACHT (domain), neuronal apoptosis inhibitor protein (NAIP), MHC-Class II transactivator/ transcription activator (CIITA), plant het product (HET-E), and telomerase-associated protein 1 (TP1) protein, NLRP3 nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3, PI, phosphatidylinositol-4-phosphate, PYD pyrin domain, P2X7R P2X purinoceptor, ROS reactive oxygen species, TLR4 Toll-like receptor 4. Note: This figure is modified from Fig. 2.1 (including the legend with Refs. and based on findings of Chen and Chen [70]) published in Ref. [11] (Section 2.2.5.3, p. 20). Further Sources: [–69].
Fig. 5
Fig. 5. A Tentative model of severity classification of respiratory viral infections, exemplarily related to COVID-19—with respect to gradually increasing strength in DAMPs emission with concomitant decreasing strength in SAMPs production.
The Berlin classification of ARDS is set in relation to the WHO criteria [97, 98]. For details of the feed–forward–loop, see Fig. 7.
Fig. 6
Fig. 6. Simplified schematic diagram of a narrative model of the action of DAMPs and SAMPs in respiratory virus-induced acute lung injury.
Injury-induced DAMPs (e.g., released from type 1 alveolar epithelial cells succumbing to RCD) activate PRR-bearing innate immune cells such as alveolar epithelial cells and resident alveolar macrophages, which secrete a first wave of cytokines. Subsequently, these inflammatory mediators amplify the inflammatory response via recruitment of further innate immune/proinflammatory cells such as PMNs and M1-like macrophages, which in turn intensify acute pulmonary inflammation via secretion of further proinflammatory mediator substances (e.g., cytokines). Pulmonary inflammation resolution is initiated by a switch of the PMN phenotype and shift of M1-like to M2-like macrophages, whereby SAMPs, mainly secreted by injury-activated M2-like macrophages, less neutrophils, contribute to resolution via promotion of antiinflammatory mechanisms (e.g., production of IL-10), efferocytosis, and reepithelialization—the end result being repair of the alveolar barrier. AECI alveolar epithelial type I cells, AECII alveolar epithelial type II cells, ECM extracellular matrix, MØ macrophage, PMN polymorphonuclear leukocytes, RCD regulated cell death. Note: Co-activating virus-associated MAMPs are not shown. Also note: injured alveolar epithelial type I cells are representative for other injured cells such as alveolar epithelial type II cells and endothelial cells. In particular, the target role of the endothelium is not shown. Sources: The figure is slightly modified from Ref. [11]; further Refs. [119, 138].
Fig. 7
Fig. 7. Simplified schematic diagram of a conceptual “feed-forward-loop” model of DAMP-induced cytokine storm in respiratory viral infection.
Virus-induced RN (necroptosis and pyroptosis) leads to release of constitutive DAMPs such as HMGB1 and DNA that activate PRR-bearing alveolar macrophages, which in turn secrete cytokines such as TNF and type I IFNs. These cytokines operate as inducible DAMPs to induce necroptosis. Release of constitutive DAMPs such as HMGB1 and eATP induces pyroptosis, which again is associated with release of the constitutive DAMPs and IL-1β. The constitutive DAMPs such as HMGB1 and DNA activate recruited PRR-bearing neutrophils, which contribute to further cytokine production such as TNF and type I IFNs. The sequelae of processes are repeated in terms of a feed-forward-loop and might proceed to a vicious circle. AECI alveolar epithelial type I cells, cDAMPs constitutive DAMPs, eATP extracellular ATP, HMGB1 high mobility group box 1, iDAMPs inducible DAMPs, IFN interferon, IFNAR type I interferon receptor, IL interleukin, MØ macrophage, P2XR7 purinergic receptor P2X7, RN regulated necrosis, TLR Toll-like receptor, TNF tumor necrosis factor, TNFR1 tumor necrosis factor receptor 1, vc vicious circle. Note: the oversimplified figure shows only one example out of various possible scenarios regarding release of DAMPs, expression of pattern recognition receptors, secretion of cytokines (iDAMPs), type of cells involved, and sequelae of processes. Also note: injured alveolar epithelial type I cells are representative for other injured cells such as alveolar epithelial type II cells and endothelial cells. In particular, the target role of the endothelium is not shown. Sources: [45, 121, 123].
Fig. 8
Fig. 8. Proposal of a theory.
The superimposition of respiratory virus-induced DAMPs with non-virus-induced DAMPs derived from conditions known to be associated with emission of DAMPs (e.g., high age and air pollution) contributes—via promotion of hyperinflammatory pathways—to severe and fatal courses of pneumonia, as observed in COVID-19.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Chen R, Huang Y, Quan J, Liu J, Wang H, Billiar TR, et al. HMGB1 as a potential biomarker and therapeutic target for severe COVID-19. Heliyon. 2020;6:e05672. doi: 10.1016/j.heliyon.2020.e05672. - DOI - PMC - PubMed
    1. Chen L, Long X, Xu Q, Tan J, Wang G, Cao Y, et al. Elevated serum levels of S100A8/A9 and HMGB1 at hospital admission are correlated with inferior clinical outcomes in COVID-19 patients. Cell Mol Immunol. 2020;17:992–4. Available from: http://www.nature.com/articles/s41423-020-0492-x. - PMC - PubMed
    1. Scozzi D, Cano M, Ma L, Zhou D, Zhu JH, O’Halloran JA, et al. Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19. JCI Insight. 2021. http://insight.jci.org/articles/view/143299. - PMC - PubMed
    1. Matzinger P. Tolerance, Danger, and the Extended Family. Annu Rev Immunol. 1994;12:991–1045. - PubMed
    1. Land W, Schneeberger H, Schleibner S, Illner WD, Abendroth D, Rutili G, et al. The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplant. 1994;57:211–7. doi: 10.1097/00007890-199401001-00010. - DOI - PubMed

MeSH terms