PAMPs and DAMPs in Sepsis: A Review of Their Molecular Features and Potential Clinical Implications

Abstract

Sepsis is a serious organ dysfunction caused by a dysregulated immune host reaction to a pathogen. The innate immunity is programmed to react immediately to conserved molecules, released by the pathogens (PAMPs), and the host (DAMPs). We aimed to review the molecular mechanisms of the early phases of sepsis, focusing on PAMPs, DAMPs, and their related pathways, to identify potential biomarkers. We included studies published in English and searched on PubMed^® and Cochrane^®. After a detailed discussion on the actual knowledge of PAMPs/DAMPs, we analyzed their role in the different organs affected by sepsis, trying to elucidate the molecular basis of some of the most-used prognostic scores for sepsis. Furthermore, we described a chronological trend for the release of PAMPs/DAMPs that may be useful to identify different subsets of septic patients, who may benefit from targeted therapies. These findings are preliminary since these pathways seem to be strongly influenced by the peculiar characteristics of different pathogens and host features. Due to these reasons, while initial findings are promising, additional studies are necessary to clarify the potential involvement of these molecular patterns in the natural evolution of sepsis and to facilitate their transition into the clinical setting.

Keywords: DAMPs; PAMPs; innate immunity; sepsis; septic shock.

Figure 1

Examples of TLRs’ morphology. Toll-like receptors (TLR) are membrane receptors, found both in the cellular surface (square A) where they can exist as hetero- or homodimers (TLR1, 2, 4, 5, 6, and 10), and in the intracellular compartments (square B) as homodimers (TLR3, 7, 8, 9, and 11). The different colors indicates the different structure of each receptor, and their possible combinations (e.g., the same TLR2, reported in light blue can form heterodimers with TLR1, TLR6 and TLR10 as well). They are type I transmembrane glycoproteins and share a common structure: extramembrane domain that includes the leucine-rich repeats (LRRs, yellow rhombuses) with ligand-binding function; transmembrane (or intermediate domain); intramembrane domain that includes the same Toll/IL-1R (TIR, violet ovals) domain as IL-1R, which plays a role in signal transduction through the reclamation of several adaptor molecules (blue triangle). Depending on the nature of these adaptors, TLRs signaling can be classified into myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways. Abbreviations: CpG-DNA = unmethylated cytosine-phosphate-guanine DNA; dsRNA = double stranded RNA; LPS = lipopolysaccharide; RNA = ribonucleic acid; ssRNA = single stranded RNA.

Figure 2

Interaction with LPS. TLR4 recognizes the lipopolysaccharide (LPS) in association with the myeloid differentiation factor 2 (MD2) and the LRR structural protein CD14. The LBP (LPS-binding protein) transports the LPS to the CD14 (cluster of differentiation 14) on the cell membrane of monocytes and macrophages. This interaction further promotes the heterodimerization of TLR4 and subsequent signaling. Yellow rhombuses: Leucine Rich Repeats (LRRs); violet ovals: Toll/IL-1 receptor (TIR) domain; blue triangle: adaptor molecule.

Figure 3

NLRs—(A). NLRs have a central, nucleotide-binding domain (NACHT), a C-terminus that identifies and binds the ligand, and a N-terminus with effector function which could be a CARD (caspase activation and recruitment domain) or PYR (pyrin domain) (*). The interaction with the ligand causes conformational change and oligomerization. The most characterized NLR is NLRP3. (B) NLRP3 is required for the activation of the canonical inflammosome. The first signal (priming) is the NF-kB mediated transcription of the NLRP3 gene together with pro-IL-1B and pro-IL-18. This first step may be stimulated by activation of TLRs, TNFR, and IL-1R. The second signal is mediated either by PAMPs or by transmembrane ionic fluxes, reactive oxygen species, and Golgi dispersion. This signal causes oligomerization, with activation of caspase-1, that cleaves the pro-interleukins in mature IL-1 and IL-18, and the gasdermin (GDSMD), which then forms membrane pores.

Figure 4

RLRs—The RNA helicases RIG-I, MDA5, and LGP2 interact with viral RNA (and eventually with DAMPs). While LGP2 has a regulatory function, RIG-I and MDA5 have a CARD domain. These two latter receptors interact with a mitochondrial transmembrane adaptor (MAVS) that binds the kinase TBK1 (TANK-binding kinase 1). The downstream pathway leads to inflammatory and antiviral cytokines transcription release.

Figure 5

CLRs—(A). Some CLRs have activating function (green arrow) thanks to their activating ITAM domain. This domain can be included in the intracellular tail, connected to the receptor by an adaptor, or be half-domain (HITAM). The phosphorylation of the tyrosine (green dot) causes a downstream signaling that leads to NF-κB pathway activation. (B) Other CLRs contain an inhibitory motif (ITIM) that recruits tyrosine phosphatases (red dot) to inhibit the signaling pathways (red arrow). (C) Some CLRs have neither ITAM nor ITIM domains, and their signaling is either uncharacterized or utilizes alternative pathways (question mark).

Figure 6

Temporal increase trend of some DAMPs during the first phases of sepsis—Note that, for the DAMPs for which a precise increase trend (folds from the baseline) has been reported, it has been indicated in the figure in an in-scale manner (see cfDNA, eATP, and its metabolites). For the other DAMPs, the lack of this information has been identified with “x?”. Moreover, we highlight that while, for some DAMPs, the trend even after the first days from sepsis (i.e., HMGB1, mtDNA) has been described, for others, this information is missing (dotted lines). For these reasons, the study of the precise concentration trends of DAMPs in sepsis could be an interesting field of research that could have potential important clinical implications.