Use of DAMPs and SAMPs as Therapeutic Targets or Therapeutics: A Note of Caution

  • 2020 Jun;24(3):251-262. doi: 10.1007/s40291-020-00460-z.

Walter Gottlieb Land 1 2 PMID: 32248387

PMCID: PMC7127836

DOI: 10.1007/s40291-020-00460-z

Free PMC article

Abstract

This opinion article discusses the increasing attention paid to the role of activating damage-associated molecular patterns (DAMPs) in initiation of inflammatory diseases and suppressing/inhibiting DAMPs (SAMPs) in resolution of inflammatory diseases and, consequently, to the future roles of these novel biomarkers as therapeutic targets and therapeutics. Since controlled production of DAMPs and SAMPs is needed to achieve full homeostatic restoration and repair from tissue injury, only their pathological, not their homeostatic, concentrations should be therapeutically tackled. Therefore, distinct caveats are proposed regarding choosing DAMPs and SAMPs for therapeutic purposes. For example, we discuss the need to a priori identify and define a context-dependent “homeostatic DAMP:SAMP ratio” in each case and a “homeostatic window” of DAMP and SAMP concentrations to guarantee a safe treatment modality to patients. Finally, a few clinical examples of how DAMPs and SAMPs might be used as therapeutic targets or therapeutics in the future are discussed, including inhibition of DAMPs in hyperinflammatory processes (e.g., systemic inflammatory response syndrome, as currently observed in Covid-19), administration of SAMPs in chronic inflammatory diseases, inhibition of SAMPs in hyper-resolving processes (e.g., compensatory anti-inflammatory response syndrome), and administration/induction of DAMPs in vaccination procedures and anti-cancer therapy.

For More Information: https://pubmed.ncbi.nlm.nih.gov/32248387/

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

Authors: Walter Gottlieb Land Genes & Immunity volume 22, pages141–160 (2021 )Cite this article

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.

Introduction

When the first articles on severe and fatal outcomes of COVID-19 were published, researchers worldwide working in the field of damage-associated molecular patterns (DAMPs) thought spontaneously: this is the work of DAMPs! And the researchers were surprised that most authors focused on the pathogenetic role of the “cytokine storm” observed in patients developing viral pneumonia-induced acute respiratory distress syndrome (ARDS) without discussing the fundamental part of DAMPs in initiating cytokine production. However, quite admittedly, the dataset on the pathogenetic role of DAMPs in COVID-19 is still too poor to prove their vital pathogenetic role in this challenging disease. On the other hand, there is accumulating evidence indicating that DAMPs are involved in respiratory viral disorders (as in all infectious diseases), culminating in three recent reports on their detection in COVID-19 patients [1,2,3]. This should be reason enough for a short review.

DAMPs in infectious diseases at a glance

The danger/injury model in Immunology, proposed in 1994 [45] and after that several times modified, argues that immune responses are driven by cell stress and tissue injury, including pathogen-caused stress and injury, rather than by the recognition of non-self molecules derived, for example, from pathogenic invaders. The core of this model refers to the generation and emission of DAMPs, that is, molecules that are generated, exposed, or emitted upon any stress, damage, or death of cells.

For More Information: https://www.nature.com/articles/s41435-021-00140-w

Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients

  1. Authors: Joram HuckriedeSara Bülow AnderbergAlbert MoralesFemke de VriesMichael HultströmAnders BergqvistJosé T. Ortiz-PérezJan Willem SelsKanin WichapongMiklos LipcseyMarcel van de PollAnders LarssonTomas LutherChris ReutelingspergerPablo Garcia de FrutosRobert Frithiof & Gerry A. F. Nicolaes  Scientific Reports volume 11, Article number: 15701 (2021) Cite this article

Abstract

Coronavirus disease 19 (COVID-19) presents with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels and evolution of the damage associated molecular patterns (DAMPS) cell free DNA (cfDNA), extracellular histone H3 (H3) and neutrophil elastase (NE), and the immune modulators GAS6 and AXL in relation to clinical parameters, ICU scoring systems and mortality in patients (n = 100) with severe COVID-19. cfDNA, H3, NE, GAS6 and AXL were increased in COVID-19 patients compared to controls. These measures associated with occurrence of clinical events and intensive care unit acquired weakness (ICUAW). cfDNA and GAS6 decreased in time in patients surviving to 30 days post ICU admission. A decrease of 27.2 ng/mL cfDNA during ICU stay associated with patient survival, whereas levels of GAS6 decreasing more than 4.0 ng/mL associated with survival. The presence of H3 in plasma was a common feature of COVID-19 patients, detected in 38% of the patients at ICU admission. NETosis markers cfDNA, H3 and NE correlated well with parameters of tissue damage and neutrophil counts. Furthermore, cfDNA correlated with lowest p/f ratio and a lowering in cfDNA was observed in patients with ventilator-free days.

Introduction

In severe cases, COVID-19 disease develops into acute respiratory distress syndrome (ARDS), an acute lung injury causing patients to be dependent of ventilator support, which may be accompanied by development of multiple organ failure (MOF)1. Mortality is seen primarily in patients over the age of 652,3,4,5 and is highest for infected individuals with underlying comorbidities such as hypertension, cardiovascular disease or diabetes6,7,8. For patients who are taken into the intensive care unit (ICU), a high SOFA (sequential organ failure assessment) score and increased levels of fibrin D-dimers have been reported9 to associate with poor prognosis. Thromboembolic complications develop in 35–45% of COVID-19 patients10, including thrombotic microangiopathies and disseminated intravascular coagulation (DIC) reminiscent of bacterial sepsis. Yet, COVID-19 has distinct features11 that point at a somewhat different pathological mechanism. The involvement of immune regulatory and hemostatic pathways appears evident, and recent findings have confirmed that the innate immune system and more in particular neutrophil extracellular traps (NETs) play a role in COVID-19 disease pathogenesis. NETs, networks of DNA fibers that are decorated with proteins such as histones and elastase, are released from neutrophils to bind and neutralize viral proteins, bacteria and fungi12. While extracellular histones and NE serve a protective, antimicrobial function, they are potentially harmful to the host.

NETs are abundant in lung capillaries13 and are known to be pro-coagulant due to their intrinsic capacity to activate platelets14.

Excessive NET production, initiated by several pathways that also include complement activation13, results in collateral damage to lung tissues, a disturbed microcirculation of the lung15, loss of alveolar-capillary barrier function and further release of pro-inflammatory cytokines16.

During the preparation of this work it was reported that cellular components that are released upon cellular disruption, so-called damage associated molecular patterns (DAMPs) and NETosis are involved in COVID-19 disease1718. This is fully in line with the observation that in ARDS, NETs contribute to disease progress19. Extracellular histones are cytotoxic DAMPs irrespective of their origin. They may appear during NETosis12,14,20 or originate from damaged tissues21, while cell free DNA (cfDNA) and the protease neutrophil elastase (NE) are released concomitantly22. Cellular free deoxyribonucleic acid (cfDNA) and histones promote proinflammatory cytokine release23,24. Histones have been shown to activate and recruit leukocytes25, damage alveolar macrophages26, activate erythrocytes27, epithelial and endothelial cells, in particular pulmonary endothelial cells28,29,30. If not cleared from circulation, cfDNA as well as histones facilitate severe systemic inflammation and worsen the clinical condition31,32. Presence of NE in plasma is associated with exacerbations, lung function decline and disease severity in patients with chronic obstructive pulmonary disease (COPD), bronchiectasis and cystic fibrosis33,34,35 and decrease of NE levels in bronchiectasis patients improved lung function and airway inflammation36.

At the same time that it provides a first line of defense against infections, the innate immune system initiates self-control responses to prevent damage to the host. One mechanism involved in early immunomodulation is the growth arrest-specific 6 (GAS6)/TAM ligand/receptor system37,38. The GAS6/AXL axis regulates the immune response by modulating cytokine production, inducing a reparative cellular response and by mediating efferocytosis, removing irreversibly damaged cells. The system also provides a mechanism of regulating endothelial and platelet activation and interaction39. Plasma concentrations of GAS6 and AXL increase in a diverse spectrum of inflammatory conditions40, including sepsis and septic shock; but also systemic inflammatory response syndrome (SIRS) without infection41. In several studies, GAS6 at IC admission correlated with severity of organ damage (i.e. SOFA) or with damage of specific organs41,42,43,44,45. This is also the case in viral infections46. These studies illustrate the modulatory role of the innate response provided by GAS6 and suggest that the presence of these components in plasma could be an early event in the orchestration of the immune response to viral infections.

cfDNA, extracellular histones and GAS6 are implicated in regulation of inflammatory and hemostatic pathways in the context of severe viral infections and ARDS, all of which are implicated in COVID-19. While other studies have reported the presence of DAMPs and NETosis markers in smaller COVID-19 populations, here we study a group of 100 severely ill COVID-19 patients admitted to the intensive care unit (ICU). Our hypothesis was twofold:

First, cfDNA, NE, histones and GAS6/AXL are activated in severe COVID-19. Second, cfDNA, NE, histones and GAS6/AXL are related to the severity of illness and reflect organ dysfunction in severe COVID-19.

For More Information: https://www.nature.com/articles/s41598-021-95209-x

Inflammasome activation at the crux of severe COVID-19

Authors: Setu M. Vora,1,2Judy Lieberman,2,3 and Hao Wu1,2

Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in life-threatening disease in a minority of patients, especially elderly people and those with co-morbidities such as obesity and diabetes. Severe disease is characterized by dysregulated cytokine release, pneumonia and acute lung injury, which can rapidly progress to acute respiratory distress syndrome, disseminated intravascular coagulation, multisystem failure and death. However, a mechanistic understanding of COVID-19 progression remains unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates inflammasomes, which are large multiprotein assemblies that are broadly responsive to pathogen-associated and stress-associated cellular insults, leading to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and pyroptosis, an inflammatory form of cell death. We further discuss potential mechanisms of inflammasome activation and clinical efforts currently under way to suppress inflammation to prevent or ameliorate severe COVID-19.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has so far infected more than 190 million people and caused death of more than 4.1 million people worldwide. The virus primarily infects the respiratory tract, causing fever, sore throat, anosmia and dyspnoea, but its tissue tropism still remains to be fully understood. As many as 10–15% of patients develop severe pneumonia, with some cases progressing to hypoxia and acute respiratory distress syndrome (ARDS), which requires mechanical ventilation in a critical care setting and has high mortality. Patients can also develop multi-organ failure, acute kidney injury and disseminated intravascular coagulation, among a host of other disorders111. Aside from supportive care, only a few treatments have been approved for COVID-19, and their reduction of mortality has been limited1214. Although several vaccines against SARS-CoV-2 have been approved and are being administered internationally, there will still be a significant number of infections owing to people who are not vaccinated in regions with inadequate access or acceptance of vaccination. In addition, while global vaccination efforts strive to meet the challenge of ending the pandemic, the appearance of immune-evasive viral variants and the unlikelihood of reaching immediate herd immunity underscore the continued need for additional treatments mitigating disease progression1519.

Most researchers agree that an inappropriate hyperinflammatory response lies at the root of many severe cases of COVID-19, driven by overexuberant inflammatory cytokine release. Consistently, co-morbidities, such as obesity, diabetes, heart disease, hypertension and ageing, which are prognostic of poor outcome, are associated with high basal inflammation7,11,20,21. It has been proposed since the beginning of the pandemic that these co-morbidities and the ensuing hyperinflammatory response may be aetiologically linked through overactive inflammasome signaling, which may account for the association of these co-morbidities with severe COVID-19 in the context of chronic inflammation as well as for COVID-19 progression in the context of a robust acute inflammatory response to infection2229. However, many of the studies that seek to understand the immune response to SARS-CoV-2 are based on RNA sequencing, often of thawed cells, and infected, activated or dying cells do not survive freeze–thaw well, which could skew results. Moreover, inflammasome activation does not directly induce transcriptional responses, and its detection is less straightforward than that of most other signaling pathways. Nonetheless, several studies are now accumulating that support direct (infection-induced) and indirect inflammasome activation and the critical role of inflammasomes in severe COVID-19. Here we discuss the available evidence, potential mechanisms and the implications for therapy.

Key to inflammation and innate immunity, are large, micrometer-scale multiprotein cytosolic complexes that assemble in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and trigger proinflammatory cytokine release as well as pyroptosis, a proinflammatory lytic cell death30,31 (Fig. 1). Upon activation by PAMPs or DAMPs, canonical inflammasome sensors — mainly in monocytes, macrophages and barrier epithelial cells — oligomerize and recruit the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) to form inflammasome specks, within which the inflammatory caspase 1 is recruited and activated. Inflammasome sensors are activated in response to different triggers and differ in their overall specificities to PAMPs or DAMPs. NLRP3, the most broadly activated inflammasome sensor and a member of the nucleotide-binding domain- and leucine-rich repeat-containing protein (NLR) family, responds to an array of insults to the cell that cause cytosolic K+ efflux, Ca2+ cytosolic influx or release of mitochondrial reactive oxygen species (ROS)31,32. These insults include extracellular ATP, membrane permeabilization by pore-forming toxins and large extracellular aggregates such as uric acid crystals, cholesterol crystals and amyloids30. Other sensors, such as AIM2 and NLRC4, are tuned to recognize specific PAMPs and DAMPs, such as cytosolic double-stranded DNA and bacterial proteins, respectively31. In a parallel pathway, the mouse inflammatory caspase 11 and human caspase 4 and caspase 5 sense PAMPs and DAMPs such as bacterial lipopolysaccharide (LPS) that gain cytosolic access and endogenous oxidized phospholipids, leading directly to membrane damage or pyroptosis, and secondary K+ efflux followed by noncanonical NLRP3 inflammasome activation3336.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351223/