Diseases Implicated in Pathology via NOD1 and NOD2 Activation

Bacterial Infections:
NOD1 and NOD2 are intracellular pattern recognition receptors that detect conserved peptidoglycan motifs from bacterial cell walls. NOD1 recognizes γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) mainly from Gram-negative bacteria, while NOD2 detects muramyl dipeptide (MDP) present in both Gram-positive and Gram-negative bacteria. Upon ligand binding, both receptors activate the RIPK2 kinase, triggering NF-κB and MAPK signaling cascades that lead to the production of proinflammatory cytokines such as IL-1β, IL-6, and TNFα. In diseases like tuberculosis and leprosy, NOD2 contributes to granuloma formation and host defense but also promotes tissue damage when overstimulated. NOD polymorphisms have been associated with susceptibility to intracellular bacterial infections and can influence cytokine profiles, potentially exacerbating immunopathology.

Inflammatory Bowel Disease (IBD):
NOD2 is one of the most strongly associated genetic loci for Crohn’s disease. Loss-of-function mutations in NOD2 impair the recognition of bacterial MDP in intestinal epithelial cells and Paneth cells, leading to defective antimicrobial peptide secretion and dysbiosis. This results in chronic immune activation and Th1/Th17 polarization in the gut mucosa. Conversely, gain-of-function or hyperactive NOD signaling may exacerbate mucosal inflammation via excessive cytokine and chemokine production. In ulcerative colitis, the role of NOD1/2 is less clear but likely contributes to epithelial barrier dysfunction and proinflammatory signaling.

Rheumatoid Arthritis (RA):
NOD2 expression is elevated in synovial tissues of RA patients, and bacterial peptidoglycan components are known to exacerbate joint inflammation through NOD1/2 signaling. Activation of NODs in synovial macrophages leads to upregulation of MMPs, IL-6, and TNFα, driving pannus formation and cartilage destruction. Animal models of arthritis demonstrate that intra-articular injection of NOD ligands exacerbates disease severity, whereas inhibition of RIPK2 can reduce joint swelling and bone erosion.

Multiple Sclerosis (MS):
NOD2 activation in CNS-resident microglia and infiltrating macrophages contributes to demyelination and neuroinflammation in MS. NOD ligands have been shown to exacerbate experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, through induction of IL-23 and GM-CSF, promoting pathogenic Th17 cell responses. NOD signaling also synergizes with TLRs to amplify neuroinflammatory cascades. Variants in NOD2 may influence susceptibility to MS, although findings are not yet conclusive.

Systemic Lupus Erythematosus (SLE):
In lupus, NOD signaling contributes to inflammasome activation and sustained production of IL-1β and type I interferons. NOD1/2 expression is increased in monocytes from patients with active disease, and stimulation with bacterial products enhances the autoimmune response. The interaction between microbial exposure, gut permeability, and NOD2-driven immune responses is an area of active research.

Type 2 Diabetes and Obesity:
Low-grade chronic inflammation in metabolic tissues can be driven by NOD1 and NOD2 activation in response to gut-derived bacterial peptidoglycans. In obese individuals, increased intestinal permeability allows translocation of bacterial components into circulation, activating NOD1 in adipose tissue macrophages and hepatocytes. This promotes IL-6 and TNFα production, insulin resistance, and adipocyte dysfunction. NOD1-deficient mice are protected from high-fat-diet-induced insulin resistance and show improved glucose tolerance and reduced adipose inflammation. NOD2 may have both protective and proinflammatory roles depending on context.

Atherosclerosis:
Vascular endothelial cells and macrophages express NOD1 and NOD2, and their activation promotes endothelial dysfunction, foam cell formation, and vascular inflammation. NOD1 activation has been shown to induce VCAM-1 expression and oxidative stress in endothelial cells, while NOD2 contributes to plaque destabilization through cytokine and MMP release. RIPK2 inhibition in atherosclerotic models reduces plaque burden and improves vascular integrity, highlighting NOD signaling as a contributor to cardiovascular risk.

Alzheimer’s Disease (AD):
Chronic activation of microglia via NOD2 contributes to neuroinflammation in Alzheimer’s disease. Amyloid-β aggregates may indirectly stimulate NOD pathways through secondary bacterial translocation or by releasing danger-associated molecular patterns (DAMPs) that synergize with NOD signaling. NOD2 activation promotes production of IL-1β, TNFα, and reactive oxygen species, which impair synaptic plasticity and accelerate neuronal loss. NOD inhibition in AD mouse models reduces glial activation and improves cognitive performance.

Parkinson’s Disease (PD):
Gut-brain axis disruption in PD involves microbial dysbiosis and increased gut permeability, leading to enhanced NOD1/2 signaling in the enteric nervous system and systemic circulation. This triggers chronic peripheral inflammation that contributes to α-synuclein aggregation and neurodegeneration. NOD2 is expressed in microglia and intestinal macrophages; its activation has been linked to elevated IL-6 and TNFα in the substantia nigra and gut mucosa of PD models. Therapeutic modulation of gut microbiota or NOD pathways may reduce neuroinflammatory burden in PD.

Major Depressive Disorder (MDD):
NOD1 and NOD2 are involved in inflammation-related depression through their ability to detect circulating bacterial peptidoglycans and activate NF-κB via RIPK2. This leads to systemic release of IL-6, TNFα, and IL-1β, which are known to interfere with monoaminergic neurotransmission and hippocampal neurogenesis. Animal models demonstrate that NOD1 activation induces anhedonia and behavioral despair, while NOD1 or RIPK2 deficiency confers resistance to stress-induced depressive behaviors. These pathways link peripheral microbial signals to central mood-regulating circuits.

Schizophrenia:
NOD signaling may contribute to the neurodevelopmental and immune abnormalities observed in schizophrenia. Prenatal exposure to NOD2 ligands (e.g., muramyl dipeptide) results in offspring with schizophrenia-like phenotypes, including impaired social interaction and disrupted cortical structure. These changes are associated with persistent microglial activation and altered synaptic pruning. Elevated expression of NOD2 and downstream cytokines such as IL-1β and IL-6 has been observed in some patients, suggesting that NOD-driven inflammation may influence disease trajectory.

Bipolar Disorder (BD):
During manic episodes, increased NOD1/2 signaling and associated cytokine production have been reported in BD patients. NOD activation may contribute to mitochondrial dysfunction, oxidative stress, and glutamate excitotoxicity—mechanisms implicated in mood instability. NOD1 stimulation in animal models leads to hyperactivity and altered circadian gene expression. Gut dysbiosis and increased bacterial translocation during mood episodes may further enhance NOD pathway activation, linking immune perturbation to behavioral symptoms.

Autism Spectrum Disorder (ASD):
NOD2 has been implicated in maternal immune activation models of ASD. Prenatal exposure to MDP results in elevated IL-6 and IL-17 production, microglial priming, and neurodevelopmental abnormalities in offspring. These include impaired synaptogenesis, altered cortical architecture, and ASD-like behaviors. Postmortem studies of ASD brains have shown elevated NOD2 and glial activation markers. Gastrointestinal symptoms and increased intestinal permeability common in ASD may promote chronic NOD stimulation and sustained neuroimmune activation.