Charting the nerve–immune axis in endometriosis

Tianyi Lu; Zhengrong Deng; Kailin Yang; Shengtao Zhou

doi:10.1016/j.it.2026.01.005

Endometriotic lesions exhibit significant hyperinnervation and a dysregulated immune microenvironment, with colocalization of nerves and immune cells (especially macrophages, mast cells, etc.).Calcitonin gene-related peptide released by transient receptor potential vanilloid 1-positive sensory neurons promotes lesion growth and pain sensation by recruiting macrophages via receptor activity-modifying protein 1 and exerting pro-angiogenic effects.Activated neurons promote immune cell recruitment and activation by releasing neuropeptides (e.g., substance P and calcitonin gene-related peptide). Reciprocally, immune cells secrete neurotrophic factors (e.g., nerve growth factor and brain-derived neurotrophic factor) that stimulate nerve fiber proliferation and sensitization, forming a positive feedback loop.Proliferation and activation of microglia, astrocytes, and mast cells occur in the brain and spinal cord of patients with endometriosis, contributing to central sensitization. Chronic pain and lesion growth in endometriosis are fueled by aberrant neuroimmune communication. A self-perpetuating cycle exists: immune cells secrete neurotrophic factors, driving abnormal nerve growth, sensitization, and inflammation. Activated sensory neurons release neuropeptides that recruit and activate immune cells. Disrupting this neuroimmune dialog presents a new therapeutic strategy for endometriosis. Endometriosis is increasingly recognized as a systemic disorder involving complex interactions between nerves and immune cells, driving chronic pain and inflammation beyond the initial theories. Recent breakthroughs highlight aberrant sensory nerve growth and dysfunctional immune responses as key events in lesion development and sustained pain. This review systematically examines the functional link between neuroimmune interplay and endometriosis, showing how reciprocal signaling between nerves and immune cells actively shapes epithelial and stromal behavior, amplifies inflammation, and reinforces pain circuitry. Recognizing this integrated neuroimmune framework reframes endometriosis as a disorder of distributed network dysregulation and highlights that targeting key neuroimmune nodes may offer new therapeutic opportunities to curb both lesion progression and endometriosis-related chronic pain. Endometriosis is increasingly recognized as a systemic disorder involving complex interactions between nerves and immune cells, driving chronic pain and inflammation beyond the initial theories. Recent breakthroughs highlight aberrant sensory nerve growth and dysfunctional immune responses as key events in lesion development and sustained pain. This review systematically examines the functional link between neuroimmune interplay and endometriosis, showing how reciprocal signaling between nerves and immune cells actively shapes epithelial and stromal behavior, amplifies inflammation, and reinforces pain circuitry. Recognizing this integrated neuroimmune framework reframes endometriosis as a disorder of distributed network dysregulation and highlights that targeting key neuroimmune nodes may offer new therapeutic opportunities to curb both lesion progression and endometriosis-related chronic pain.

Charting the nerve–immune axis in endometriosis

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