Danger signals - damaged-self recognition across the tree of life

Abstract

Multicellular organisms suffer injury and serve as hosts for microorganisms. Therefore, they require mechanisms to detect injury and to distinguish the self from the non-self and the harmless non-self (microbial mutualists and commensals) from the detrimental non-self (pathogens). Danger signals are "damage-associated molecular patterns" (DAMPs) that are released from the disrupted host tissue or exposed on stressed cells. Seemingly ubiquitous DAMPs are extracellular ATP or extracellular DNA, fragmented cell walls or extracellular matrices, and many other types of delocalized molecules and fragments of macromolecules that are released when pre-existing precursors come into contact with enzymes from which they are separated in the intact cell. Any kind of these DAMPs enable damaged-self recognition, inform the host on tissue disruption, initiate processes aimed at restoring homeostasis, such as sealing the wound, and prepare the adjacent tissues for the perception of invaders. In mammals, antigen-processing and -presenting cells such as dendritic cells mature to immunostimulatory cells after the perception of DAMPs, prime naïve T-cells and elicit a specific adaptive T-/B-cell immune response. We discuss molecules that serve as DAMPs in multiple organisms and their perception by pattern recognition receptors (PRRs). Ca(2+)-fluxes, membrane depolarization, the liberation of reactive oxygen species and mitogen-activated protein kinase (MAPK) signaling cascades are the ubiquitous molecular mechanisms that act downstream of the PRRs in organisms across the tree of life. Damaged-self recognition contains both homologous and analogous elements and is likely to have evolved in all eukaryotic kingdoms, because all organisms found the same solutions for the same problem: damage must be recognized without depending on enemy-derived molecules and responses to the non-self must be directed specifically against detrimental invaders.

Keywords: DAMP; damage-associated molecular pattern; danger model; immunity; injury; non-self; wounding.

FIGURE 1

Damaged-self recognition. The disintegration of cells (left) releases intracellular molecules to the extracellular space and exposes macromolecules to hydrolytic enzymes from which they are separated in the intact cell. In principle, all these delocalised and newly produced molecules can serve as damage-associated molecular patterns (DAMPs) that prepare the neighboring, intact cell (right) for enemy recognition and wound sealing.

FIGURE 2

The danger model. (A) Main players of the (strongly simplified) danger model are the T-helper cell (T), the B-lymphocyte (B), and the dendritic cell (DC). (B) A somatic cell (SC) becomes destructed and releases DAMPs. The perception of these DAMPs causes the DC to mature to become an antigen-presenting cell (APC) and, thereby, gain immunostimulatory capacities. (C) An activated DC acts as APC and presents the antigen (Ag) to a naive T-cell. (D) The activated T-cell helps the B-lymphocyte, which thereby survives the recognition of the antigen. After Matzinger (2002).

FIGURE 3

MAPKs in the DAMP perception in innate immune cells. DAMPs interact with multiple PRRs of innate immune cells and trigger the maturation of DC to mature APCs or the synthesis and release of Type I interferons (IFNs), cytokines, chemokines, and other pro-inflammatory compounds. Toll-like receptors (TLRs) such as TLR2 or TLR4 are located on the outer membrane, sense class I DAMPs (such as HMGB1) and initiate a pathway dependent on MyD88 and other mediators that triggers cascades that depend on mitogen-activated protein kinases, MAPKs (among others) and activate NF-κB and other transcription factors (TF). Nucleic acids can also be sensed via TLRs 3,7,8,9, which are located on the endosomal membrane, and activate the same downstream pathways.

FIGURE 4

Two-step activation by DAMPs of the NLRP3-inflammasome in mammalian macrophages. The priming phase (A) is characterized by the perception of class I DAMPs such as HMGB1 by TLRs, which induces transcription-mediated up-regulation of the NLRP3 receptor (sensor!) and the synthesis of pro-interleukin 1β (pro-IL-1β). Finite activation of the inflammasome (B) occurs when DAMPs of various classes are directly or indirectly sensed by NLRP3. Among other mechanisms, the release of phagocytosed DAMPs from lysosomes and the resulting intracellular formation of reactive oxygen species (ROS), K⁺ efflux and Ca²⁺ influx, and the interaction of eATP with its receptor (P2X7R), all trigger assembly and activation of the inflammasome and subsequent synthesis of IL -1β, which interacts with interleukin receptor 1 (IL -1R) to activate TF such as NF-κB, resulting in the production of further proinflammatory substances to create full-scale tissue inflammation. See text for details.

FIGURE 5

Putative mechanisms for DAMP perception in plants. Wounding activates the MAPKs, WIPK, and SIPK, likely via the perception of different DAMPs by as yet unknown pattern recognition receptors (PRRs). These kinases trigger the synthesis of jasmonic acid (JA) in the chloroplast. JA is conjugated to form JA-isoleucine (Ja-Ile), which interacts with its receptor, the F-box protein, COI1. JA-Ile specifically binds to COI1 protein and thereby promotes binding of COI1 to JASMONATE ZIM-DOMAIN (JAZ) proteins, which represent repressors of JA-induced responses in plants. This binding event facilitates the ubiquitination of JAZs by the SCF^COI1 ubiquitin ligase, which leads to the subsequent degradation of JAZs and the release of TF, such as MYC2, and the consecutive expression of JA-responsive genes. Alternatively, Ca²⁺-influxes which can, among others be triggered by the perception of eATP by the DORN1 receptor, initiate the formation of ROS by NADPH oxidase, downstream MAPK signaling cascades and consecutive activation of the same genes via as-yet unknown TF. After Wu and Baldwin (2010).