Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach

Abstract

Two prominent models emerged as a result of intense interdisciplinary discussions on the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept that links a molecular initiating event to the adverse outcome via key events. Here, evidence is discussed, suggesting that environmental stress/injury-induced damage-associated molecular patterns (DAMPs) may operate as an essential integrating element of both environmental health research paradigms. DAMP-promoted controlled/uncontrolled innate/adaptive immune responses reflect the key events of the AOP concept. The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. Clinical examples of such a scenario are briefly sketched, in particular, a model in relation to the emerging COVID-19 pandemic, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs.

Keywords: Adverse outcome pathway; COVID-19; DAMPs; Exposome; Innate immunity.

Fig. 1

Conceptual scenario model of excessive DAMPs emission that may avalanche-like develop into a chain of five lines of different DAMPs, promoting and expanding acute local/systemic hyperinflammatory responses. Clinically, these processes manifest as acute solid organ failure and/or systemic inflammatory response syndrome, which may lead to multiple organ dysfunction syndrome. aiic activated innate immune cells, cDAMPs constitutive DAMPs, HMGB1 high mobility group box 1, iDAMPs inducible DAMPs, IFN interferon, MODS multiple organ dysfunction syndrome, mtDNA mitochondrial DNA, RN regulated necrosis, stress resp stress responses, SIRS systemic inflammatory response syndrome, TNF tumor necrosis factor, TXNIP thioredoxin-interacting protein. Source: The figure was published in Land (2018)

Fig. 2

Schematic representation of a simplified narrative scenario model of integrating DAMP-promoted innate and adaptive immune responses (in terms of uncontrolled, dysregulated responses) in both the exposome and the AOP concept. Any infectious or sterile stress/injury (i.e., environmental stressors) are mediated (1) directly by exogenous DAMPs, or (2) indirectly by stress/injury-induced endogenous DAMPs, which interact with PRMs on or in cells of the innate immune system (in the case of infectious injury, together with MAMPs). Following recognition of DAMPs (plus MAMPs, respectively), PRM-bearing cells get activated to trigger innate immune inflammatory responses or, in the presence of nonself or altered-self antigens, to promote antigen-specific adaptive immune responses. DAMP-triggered innate immune effector responses, when uncontrolled and dysregulated, result in pathologies such as acute/chronic (auto)inflammatory diseases, DAMP-shaped, antigen-specific adaptive immune responses, when uncontrolled and dysregulated, can lead to immune pathologies such as autoimmune or allergic diseases. Totality: all environmental chemicals acting as stressors (“stressogens”) on a particular receptor or biological pathway in a functional assay [according to Smith et al. (2015)]. AO adverse outcome, AOP adverse outcome pathway, APCs antigen-presenting cells, CTLs cytotoxic T lymphocytes, DAMPs damage-associated molecular patterns, DCs dendritic cells, KE key event, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, MØ macrophages, PMNs polymorphonuclear neutrophils, PRMs pattern recognition molecules. Sources: Smith et al. (2015), Escher et al. (2017), Leist et al. (2017) and Vinken et al. (2017)

Fig. 3

Schematic representation of a narrative scenario model of controlled homeostatic DAMP-promoted pathways in light of the exposome and AOP concepts. The figure shows the first part of key events (KEs). The initiating event expressed by DAMPs↔PRMs interaction (MIE) leads to a sequential cascade of cellular, tissue, and organ responses (key events = KEs), linked to each other by key event relationship (KER). DAMP-promoted, failing (!) stress responses (KE_1–n) result in subroutines of regulated cell death (KE_2–n) that are associated with release of DAMPs. DAMPs (together with MAMPs in case of infectious injury) are sensed by PRMs to trigger activation of innate immune cells (KE_3–n), which trigger the fourth key event in terms of innate immune inflammatory responses. AO adverse outcome, AOP adverse outcome pathway, DAMPs damage-associated molecular patterns, DCs dendritic cells, DDR DNA damage response, ECs endothelial cells, EpCs epithelial cells, HSR heat shock response, KE key event, KER key event relationship, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, MØ macrophages, PMNs polymorphonuclear neutrophils, PRMs pattern recognition molecules, RCD regulated cell death, UPR unfolded protein response. Sources: Smith et al. (2015), Escher et al. (2017), Leist et al. (2017) and Vinken et al. (2017)

Fig. 4

This figure is the continuation of Fig. 3 and shows the second part of key events resulting in homeostasis, whereby two phases of events (MIE and KE_4→n) are depicted again. Thus, the fourth inflammatory event proceeds to SAMP-driven resolution of inflammation (KE_5–n), associated with MAMP/DAMP-promoted induction of an innate immune memory (KE_6–n), finally resulting in homeostasis. DAMPs damage-associated molecular patterns, HO homeostasis, KE key event, KER key event relationship, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, PMNs polymorphonuclear neutrophils, PRMs pattern recognition molecules, SAMPs suppressing DAMPs. Sources: Smith et al. (2015), Escher et al. (2017), Leist et al. (2017) and Vinken et al. (2017)

Fig. 5

Schematic representation of a simplified narrative scenario model of uncontrolled dysregulated, DAMP-promoted pathways in light of the exposome and AOP concepts. The figure illustrates the sequelae of key events proposed to leading to ARDS and SIRS, reflecting the adverse outcome in COVID-19. The promoted dysregulated pathways leading to COVID-19 starts with the sequelae of events (MIE → KE_4→n) as described for the controlled pathway (Fig. 3). However, instead of proceeding to homeostatic events, the DAMP-induced pathways now provoke “pathogenic” KEs key events resulting in ARDS and/or SIRS/sepsis. The triggering “aberrant” event is the fifth KE that refers to pulmonary hyperinflammation, as characterized by intrapulmonary emission of DAMPs in excessive, which may spread out systemically. The adverse outcomes refer to ARDS and/or SIRS/sepsis. AO adverse outcome, ARDS acute respiratory distress syndrome, DAMPs damage-associated molecular patterns, KE key event, KER key event relationship, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, PRMs pattern recognition molecules, SIRS systemic inflammatory response syndrome. Source: Land (2018)

Fig. 6

Schematic representation of a simplified narrative scenario model of uncontrolled dysregulated, DAMP-promoted pathways in light of the exposome and AOP concepts. The figure illustrates the sequelae of key events proposed to leading to immune disorders, reflecting the adverse outcome. The stress/injury → DAMP-promoted, dysregulated pathways leading to immune diseases start with the sequelae of events (MIE → KE_3→n) as described for the controlled pathway (Fig. 3). However, instead of proceeding to homeostatic events, the DAMP-induced pathways now provoke “pathogenic” KEs key events resulting in an AO in terms of immune disorders such as autoimmune or allergic diseases. Ag antigen, AO adverse outcome, CTLs cytotoxic T cell lymphocytes, DAMPs damage-associated molecular patterns, DCs dendritic cells, KE key event, KER key event relationship, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, PRMs pattern recognition molecules. Sources: Land (2018), Smith et al. (2015), Escher et al. (2017), Leist et al. (2017) and Vinken et al. (2017)

Fig. 7

Schematic representation of a simplified narrative scenario model of uncontrolled dysregulated DAMP-promoted pathways in light of the exposome and AOP concepts. The figure illustrates the sequelae of key events proposed to leading to fibrotic disorders (organ fibrosis), reflecting the adverse outcome. The stress/injury → DAMP-promoted dysregulated pathways leading to immune diseases start with the sequelae of events (MIE → KE_3→n) as described for the controlled pathway (Fig. 3). However, instead of proceeding to homeostatic events, the DAMP-induced pathways now provoke “pathogenic” KEs key events resulting in an AO in terms of fibrotic disorders. The triggering “aberrant” event is the fifth KE that refers to (uncontrolled) chronic inflammation as characterized by the failure of an inflammation-resolution response (= “nonresolving inflammation”), proceeding to fibrogenic responses (fibrogenesis). The adverse outcome refers to complete organ fibrosis associated with typical organ-specific clinical symptoms. AO adverse outcome, DAMPs damage-associated molecular patterns, ECM extracellular matrix, HSCs hepatic stellate cells, KE key event, KER key event relationship, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, PRMs pattern recognition molecules, SAMPs suppressing DAMPs, TGF-β transforming growth factor-beta. Source: Land (2018)

Fig. 8

Schematic representation of a simplified narrative scenario model of uncontrolled dysregulated DAMP-promoted pathways in light of the exposome and AOP concepts. The figure illustrates the sequelae of key events proposed to leading to cancer, reflecting the adverse outcome. The stress/injury → DAMP-promoted, dysregulated pathways leading to immune diseases start with the sequelae of events (MIE → KE_3→n) as described for the controlled pathway (Fig. 3). However, instead of proceeding to homeostatic events, the DAMP-induced pathways now provoke “pathogenic” KEs key events resulting in an adverse outcome in terms of cancer. The triggering “aberrant” event is the fifth KE that refers to (uncontrolled) chronic inflammation as characterized by the failure of an inflammation-resolution response. However, the exact mechanisms underlying chronic inflammatory microenvironment-promoted carcinogenesis are not fully understood. AO adverse outcome, cell./hum. cellular/humoral, DAMPs damage-associated molecular patterns, KE key event, KER key event relationship, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, PRMs pattern recognition molecules, SAMPs suppressing DAMPs. Sources: Balkwill and Mantovani (2001), Hecht (2002), Grivennikov et al. (2010), Ben-Neriah and Karin (2011), Wang et al. (2016) and Zhang and Xu (2017)