Decoding PAMPs and DAMPs: pathways from acute to chronic inflammation

The innate immune system detects danger through two broad classes of signals: pathogen-associated molecular patterns (PAMPs), conserved microbial structures such as lipopolysaccharide, flagellin and microbial nucleic acids, and damage-associated molecular patterns (DAMPs), endogenous molecules such as HMGB1, ATP, mitochondrial DNA and S100 proteins released by stressed or dying cells. Both are read by the same families of pattern recognition receptors, including Toll-like receptors, NOD-like receptors, RIG-I-like receptors and C-type lectin receptors, and both converge on shared signalling hubs that drive inflammasome activation, cytokine release and metabolic reprogramming. For decades the two classes were studied separately, yet infection and sterile injury rarely occur in isolation. Growing evidence indicates that PAMPs and DAMPs act together, and that the composition, concentration and timing of these signals, rather than any single molecule, determine whether inflammation resolves or persists.This Research Topic addresses a central unresolved question: what trips a protective acute inflammatory response into chronic, tissue-damaging inflammation? We aim to move the field beyond single-ligand studies towards a quantitative, context-aware understanding of combined PAMP and DAMP signalling. A key issue is the widely held assumption that isolated, purified patterns reproduce their biological activity in vivo. Highly purified preparations are often weakly active on their own, which suggests that synergy, co-receptor engagement, post-translational modification and redox state are essential to their function. Contributions are encouraged that define threshold levels, dose-response relationships and temporal windows for PAMP and DAMP activity, and that use in vivo model systems, including germ-free, gnotobiotic and antibiotic-treated animals, to separate microbial from endogenous contributions. We also welcome work using single-cell and spatial transcriptomics, proteomics, metabolomics, immunochemistry, structural biology and computational modelling to map how these signals are integrated. The intended outcome is a mechanistic framework that identifies tractable therapeutic targets for modulating innate immune activation in chronic inflammatory disease.We invite submissions on molecular, cellular and functional aspects of combined PAMP and DAMP signalling, including but not limited to:• Synergistic, additive, and antagonistic interactions between PAMPs and DAMPs, and the receptor complexes involved.• Dual-function proteins and alarmins, including their evolutionary roles, receptor-dependent and independent modes of action, and involvement in disease states such as autoimmunity and cancer.• Intracellular DAMPs and organelle-derived danger signals, intracellular pathogen recognition mechanisms, and microbial strategies for evading pattern recognition.• Threshold, dose, and kinetic determinants of the transition from acute to chronic inflammation, including persistent infection, immune tolerance, and persistent low-grade sterile inflammation.• Mechanisms of sterile versus infectious injury-promoted inflammation, particularly in chronic, steady-state contexts such as metabolic diseases, age-related syndromes, cardiovascular disease, and organ-specific sterile damage.• Germ-free, gnotobiotic, and other in vivo systems that separate microbial from endogenous danger signals.• Purity, preparation, and contamination artefacts in PAMP and DAMP research, and standards for experimental reproducibility.• Structural and biochemical mechanisms of pattern recognition receptor engagement and downstream signalling cascades.• Inflammasome regulation, regulated cell death pathways, and the release kinetics of endogenous danger signals.• Immunometabolic and epigenetic reprogramming, including trained immunity and innate tolerance.• Tissue- and disease-specific contexts, such as sepsis, sterile injury, fibrosis, autoimmunity, metabolic dysfunction, and neurodegenerative disease.• Therapeutic strategies, biomarkers, and computational models targeting PAMP and DAMP pathways.We welcome Original Research, Reviews, Mini Reviews, Systematic Reviews, Methods, Brief Research Reports, Hypothesis and Theory, Perspective and Opinion articles. Descriptive studies without mechanistic or functional insight, and studies relying solely on commercially sourced ligands without purity controls, are outside the scope of this collection. Topic editors: Balachandran Ravindran, ‪Idan Cohen‬‏, Walter Gottlieb Land Source: https://www.frontiersin.org/research-topics/84981/decoding-pamps-and-damps-pathways-from-acute-to-chronic-inflammation