Danger Signals Across Human Diseases

The preceding sections have established the molecular identities, sensing mechanisms, and regulatory networks that govern PAMP and DAMP signaling under homeostatic and pathological conditions. Building upon this foundation, we now examine how these danger signals integrate into the complex pathology of human disease, including infectious disease, autoimmune disorder, malignancy, organ injury, and metabolic disease (Figure 4).

FIGURE 4: The pathological role of PAMPs and DAMPs in human diseases. PAMPs and DAMPs function as central orchestrators of disease pathogenesis through five distinct modalities. In infectious diseases, PAMPs and DAMPs trigger innate sentinels to initiate phagocytosis and inflammatory responses. In autoimmune disease, PAMPs and DAMPs function as critical amplifiers that provide autoantigen sources, propagate inflammation, and sustain chronic tissue injury. In the context of malignancy, danger signals exhibit a “double‐edged sword” duality, either fueling tumorigenesis through chronic inflammation or inhibiting it by facilitating immunogenic cell death and therapeutic responses. During organ injury, stressors such as ischemia and trauma induce the release of endogenous alarmins from dying cells, establishing pro‐inflammatory feed‐forward loops that exacerbate secondary tissue injury. In metabolic disorders, pathogenesis involves the translocation of gut‐derived PAMPs across compromised barriers and the accumulation of DAMPs following metabolic dysregulation.

Infectious Disease

Infectious diseases, despite their diverse clinical manifestations, converge on a fundamental pathophysiological principle: the host immune system's recognition of microbial non‐self‐initiates a cascade of events that must be precisely calibrated to eliminate pathogens while preserving tissue integrity. This recognition is primarily mediated by PAMPs, which serve as the requisite “first signal” for acute inflammatory activation [117]. However, as infection progresses, collateral tissue injury and cellular stress trigger the liberation of endogenous DAMPs, establishing a dynamic interplay in which exogenous and endogenous danger signals collectively shape disease outcomes [118].

The PAMP/DAMP sensing machinery plays an indispensable role in antimicrobial defense across diverse pathogens. In bacterial infections, the ALPK1‐TIFA signaling axis exemplifies a critical gatekeeper of pulmonary immunity; Burkholderia cenocepacia infection models demonstrate that ALPK1 (a PRR) deficiency markedly attenuates lung inflammation but simultaneously permits uncontrolled bacterial proliferation, underscoring the necessity of this PAMP pathway for effective host defense [14]. Among viral sensors, MDA5 deficiency similarly increases susceptibility to severe infections, highlighting the nonredundant functions of cytosolic PRRs in antiviral immunity [119]. These examples collectively illustrate that PAMP/DAMP sensing constitutes an essential first line of defense, without which pathogen containment fails.

However, the PAMP/DAMP signaling axes that drive protective immunity can also precipitate catastrophic pathology when dysregulated. For example, the NS1 protein of dengue virus mimics LPS to disrupt endothelial integrity and contribute to life‐threatening vascular leakage by engaging TLR4 [97]. Sepsis represents the ultimate manifestation of such dysregulation, in which the interplay among PAMPs, DAMPs, and inflammatory cell death pathways spirals into a self‐perpetuating systemic inflammatory response [120]. Circulating DAMPs, including extracellular HMGB1 and histones, drive concurrent activation of complement and coagulation cascades, leading to disseminated intravascular coagulation and multiple organ dysfunction syndrome [121]. This transition from protective immunity to immunopathology illustrates the double‐edged nature of danger signaling: the very mechanisms evolved to eliminate pathogens can, when overwhelming or sustained, become primary drivers of tissue destruction and mortality.

Autoimmune Diseases

Autoimmune diseases arise from the breakdown of immunological tolerance, wherein genetic susceptibility and environmental triggers converge to unleash autoreactive lymphocytes against self‐tissues, resulting in chronic inflammation and tissue injury [122]. Within this pathogenic cascade, PAMPs and DAMPs function as critical amplifiers that provide autoantigen sources, propagate inflammation, and sustain the chronic tissue injury characteristic of these disorders.

Genetic susceptibility establishes the baseline threshold for immune dysregulation. Recent evidence highlights genetic dysregulation in DAMP/PAMP‐sensing receptors as a pivotal driver of autoimmunity. Excessive TLR7 (a classic DAMP sensor) signaling triggered by self‐nucleic acid recognition has been implicated in SLE pathogenesis. Cells from patients harboring the UNC93B1 E92G variant produce elevated levels of TNF‐α and IL‐6 upon TLR7/TLR8 agonist stimulation. This E92G mutation destabilizes the UNC93B1 protein and attenuates its interaction with TLR7, leading to selective TLR7 hyperactivation accompanied by constitutive type I interferon signaling that accelerates SLE progression [123].

Microbial PAMPs serve as potent environmental catalysts that lower the threshold for autoimmune activation. For example, PAMP (such as the Epstein‐Barr virus nuclear antigen‐1) exhibits cross‐reactivity with lupus‐associated self‐antigens, leading the immune system to inadvertently target host tissues [124]. Furthermore, through engagement of pattern recognition receptors, PAMPs enhance antigen presentation and costimulatory signals, effectively providing the adjuvant activity required to break self‐tolerance [122].

DAMPs and PAMPs promote the release of autoantigens. For instance, these molecules trigger NETosis, which results in the uncontrolled release of neutrophil extracellular traps that externalize intracellular structures, serving as a concentrated source of autoantigens [125]. DAMPs themselves can also function as integral components of immunostimulatory complexes. HMGB1 released from apoptotic cells assembles into complexes with dsDNA fragments that activate autoreactive B cells [126]. The progression toward clinical autoimmunity is also fueled by the DAMP‐mediated impairment of apoptotic cell sequestration. In SLE, HMGB1 masks phosphatidylserine on the surface of dying cells, effectively blocking their recognition by phagocytes. This impaired sequestration leads to secondary necrosis, releasing nucleosomes and mtDNA that function as primary autoantigens [127].

Additionally, extensive evidence demonstrates that DAMPs amplify inflammation in autoimmune disease through receptor engagement [128, 129]. In antigen‐induced arthritis (AIA), S100A8/A9 binds Toll‐like receptors on macrophages, promoting pro‐inflammatory cytokine production [130]. Conversely, recent evidence indicates that S100A8/A9 can mitigate the severity of autoimmune arthritis by promoting the expansion and activation of myeloid‐derived suppressor cells (MDSCs) [131]. This functional dichotomy appears to be dictated by the duration of alarmin exposure in a temporally‐dependent manner. Transient stimulation of immature bone marrow‐derived dendritic cells (BMDCs) with S100A8/A9 fosters pro‐inflammatory activity. In contrast, prolonged exposure of early‐stage myeloid progenitors to DAMPs skews their development toward an immunosuppressive lineage [131]. These findings underscore the profound functional plasticity of DAMPs, in which the biological outcome is determined not only by the ligand‐receptor pair but also by the chronicity of the stimulus within the microenvironment.

Beyond immune modulation, DAMPs directly amplify tissue destruction in autoimmune disease. In arthritic contexts, S100A8/A9 stimulates chondrocytes to upregulate matrix metalloproteinases, culminating in the targeted degradation of cartilage matrix [132].

Cancer

The role of PAMPs and DAMPs in oncology is defined by a complex duality. These molecules act as double‐edged swords in malignancy, as they can either facilitate tumor growth and immune evasion, or orchestrate robust antitumor immunity [133].

Chronic liberation of DAMPs and PAMPs within established tumors often fosters an inflammatory environment that supports cancer progression. Persistent danger signaling polarizes the immune landscape toward suppression. For example, HMGB1 facilitates the recruitment and accumulation of MDSCs while concurrently inhibiting the cytotoxic function of CD8+ T cells [134, 135]. Similarly, the S100A8/A9 signaling axis facilitates tumor malignancy by driving the expansion of aberrant granulocyte‐monocyte progenitors and skewing bone marrow hematopoiesis toward a myeloid bias, which ultimately impairs T cell‐mediated anti‐tumor surveillance [136]. Intratumoral F. nucleatum drives gastric cancer immune evasion by triggering the NF‐κB signaling axis and the subsequent recruitment of tumor‐associated neutrophils [137]. Danger signals directly affect tumor and stromal cells, promoting survival and spread. In conditions like myeloproliferative neoplasms, malignant S100A8/A9 release activates TLR4 and RAGE on mesenchymal stromal cells, inducing their transformation into pro‐fibrotic myofibroblasts that create a protective survival niche for leukemic cells [138].

Conversely, when appropriately engaged, often through therapeutic intervention, DAMPs and PAMPs are essential for initiating protective anti‐tumor responses. The concept of immunogenic cell death (ICD) illustrates how danger signals license adaptive immunity [139]. Tumor cells frequently subvert immunosurveillance by limiting the release of ICD‐associated molecular patterns; specifically, the upregulation of the ENTPD1/CD39 ectonucleotidase axis by tumor cells facilitates the enzymatic depletion of extracellular ATP, thereby hampering the chemotactic recruitment of immune effectors [140]. Adynerin‐mediated induction of ICD in breast cancer cells, characterized by the surface translocation of calreticulin and the liberation of HMGB1, HSP70/90, and ATP, effectively primes the phenotypic maturation and activation of dendritic cells, ultimately augmenting the cytotoxic potency of CD8+ T lymphocytes [141]. Through ICD, dying tumor cells are effectively converted into “endogenous vaccines,” shifting the parenchymal state from an immunosuppressive source to a primary driver of T cell priming. In addition, DAMPs and PAMPs can induce “trained immunity”, an epigenetic and metabolic reprogramming of innate cells that enhances their long‐term antitumor responsiveness [142]. Exploiting these pathways has led to the development of potent immunotherapies. For instance, BCG engineered to overexpress the STING‐pathway activator c‐di‐AMP, one type of PAMP, demonstrates superior efficacy by amplifying the epigenetic modifications required for sustained anti‐tumor vigilance [143].

Organ Injury

Sterile organ injury represents a pathological continuum wherein initial tissue damage, whether from ischemia, trauma, or toxic exposure, triggers DAMP release that both signals the initial damage and amplifies subsequent tissue destruction through feed‐forward inflammatory loops. This self‐propagating mechanism explains why the severity of organ injury often exceeds what would be predicted from the initial insult alone and why limiting DAMP‐mediated amplification represents a critical therapeutic opportunity.

Ischemia‐reperfusion (I/R) injury provides a typical model for this DAMP‐driven destruction. While the ischemic phase induces profound tissue hypoxia, the subsequent restoration of blood flow paradoxically exacerbates cellular demise, a phenomenon with severe clinical implications across multiple organ systems [144]. Mechanistic studies have elucidated diverse organ‐specific DAMP pathways. In the liver, I/R challenges suppress the expression of HSPA12A, which subsequently facilitates glycolysis‐mediated HMGB1 secretion. This DAMP acts as a potent driver of macrophage chemotaxis and activation, intensifying hepatic tissue damage [145]. Within the kidney, I/R triggers the release of Peroxiredoxin 1 (Prdx1). Functioning as a canonical DAMP, Prdx1 engages the Mincle/Syk/NF‐κB signaling axis to amplify the inflammatory cascade and exacerbate acute kidney injury [146]. In ocular contexts, sudden elevations in intraocular pressure induce retinal damage and the liberation of double‐stranded DNA. This nucleic acid DAMP activates the cGAS‐STING pathway, initiating the inflammatory responses that drive the progression of acute glaucoma [147].

Metabolic Disease

Metabolic diseases, such as nonalcoholic fatty liver (NAFLD) and type 2 diabetes, represent a systemic inflammatory state where nutritional excess triggers a self‐perpetuating cycle of immunological alarm [148]. This pathological landscape is initiated by the metabolic environment itself; for instance, adipose expansion and nutrient overload compromise the intestinal barrier, leading to gut dysbiosis and the systemic translocation of microbial PAMPs [149]. Simultaneously, metabolic stress promotes a dual‐layered DAMP response: canonical alarmins are liberated through accelerated cell death, while specialized “metabolic DAMPs”, including oxLDL, uric acid, and cholesterol crystals, are generated as direct byproducts of nutrient dysregulation [71]. Once liberated, these PAMPs and DAMPs act as potent drivers of disease progression by engaging innate pattern‐recognition receptors, fueling chronic, low‐grade inflammation.

The progression from NAFLD to nonalcoholic steatohepatitis (NASH) is orchestrated by a synergistic “multi‐hit” interplay between gut‐derived PAMPs and hepatocyte‐derived DAMPs, which transform the hepatic microenvironment into a chronic inflammatory niche [150]. Chronic high‐fat intake and sedentary lifestyles drive systemic insulin resistance and intestinal dysbiosis, compromising the gut barrier and facilitating the translocation of microbial LPS into the portal circulation [149]. Upon reaching the liver, these PAMPs engage TLR4 on Kupffer cells and infiltrating monocytes, providing the primary priming signal for the NLRP3 inflammasome [151]. Concurrently, excessive free fatty acid flux induces lipotoxicity, mitochondrial oxidative stress, and subsequent hepatocyte demise via apoptosis, necroptosis, or pyroptosis [152]. This cellular injury triggers the massive liberation of endogenous DAMPs, including HMGB1, mtDNA, ATP, and cholesterol crystals, which amplify local inflammation [150]. These signals further establish a self‐perpetuating feedback loop by affecting neighboring cholesterol‐loaded hepatocytes in a paracrine way [153]. Ultimately, the convergence of these danger signals sustains an unresolved inflammatory milieu that promotes collagen deposition, vascular remodeling, and the eventual transition to cirrhosis and hepatocellular carcinoma.