The neuro-immune microenvironment of acupoints—initiation of acupuncture effectiveness

This study represents a comprehensive review of the scientific mechanisms that explain acupuncture effectiveness through analysis of the neuro-immune microenvironment of acupuncture points. The authors from the Tianjin University of Traditional Chinese Medicine systematically mapped how needle insertion and manipulation initiate specific cellular and molecular responses that mediate the therapeutic effects of acupuncture. The research examines the 409 acupuncture points documented in the classical literature, including 361 points on the 14 main meridians and 48 extra points. Point anatomy reveals a complex three-dimensional structure composed of epidermis, dermis, subcutaneous tissue, muscles, and related structures such as nerves, blood vessels, lymphatics, and tendons.

Notably, nerves are distributed more densely in point regions compared with non-point areas, with different types, quantities, and combinations of nerves varying among points. The study identifies that acupuncture functions as a benign minimal traumatic stimulus that causes local connective tissue deformation and secretion of various bioactive molecules. When the needle is inserted and manipulated, it causes fractures and even necrosis of muscle fibers, leading to accumulation of red blood cells, immune cells, and cellular fragments in the region. This process triggers an acute immune response, including leukocyte and mast cell infiltration and release of vasoactive substances such as histamine, substance P, and adenosine.

Mast cells emerge as crucial cellular participants, being 55% more densely distributed in the epidermis and dermis around acupuncture points compared with non-point regions. They aggregate near small blood vessels, small nerve bundles, and nerve endings along the direction of the meridians. Needle insertion and rotation generate shear force that activates physically sensitive channels on mast cells, promoting intracellular calcium influx and subsequent degranulation. This results in the release of neurotransmitters, hormones, and cytokines including ATP, substance P, tryptase, histamine, interleukins, and serotonin into the extracellular space.

Connective tissue undergoes significant morphological changes during acupuncture manipulation. Collagen and elastic fibers, initially coiled and organized in bundles, become spread apart, deformed, and even fractured, forming a spiral pattern with the needle at the center. These structural changes initiate peripheral cellular and molecular signal transduction, including remodeling of the fibroblast cytoskeleton and altered synthesis of various cytokines. Several cell types contribute to the microenvironment response.

Fibroblasts, the most common cells in connective tissue, respond to acupuncture rotation by doubling their cross-sectional area and deforming into sheet-like bodies. They produce pro-inflammatory factors and chemokines that attract immune cells to inflammatory regions. Keratinocytes express multiple physically and chemically sensitive receptors, acting as mechanical stimulus sensors and contributing to changes in the endocrine environment through release of HPA-axis hormones. The study identifies key signaling pathways activated by acupuncture.

cDNA microarray analyses revealed 236 altered genes and 7 corresponding pathways significantly modified, including the MAPK, P53, BCR, TCR, and TLR signaling pathways. The ERK pathway showed the most apparent changes, with increased expression of pro-inflammatory substances such as Myd88, Nfkbia, Il1b, Il6, Cxcl1, and Ccl2 at local points after acupuncture stimulation. The vascular response represents another critical component. Acupuncture causes vasodilation and increased capillary permeability, upregulating blood circulation in the point region.

This brings more immune cells including mast cells, monocytes/macrophages, and neutrophils to the points to participate in the neuro-immune network. Free ion concentrations, particularly Ca2+, K+, Na+, and Cl-, increase both cellularly and extracellularly along the meridians and at the points, with Ca2+ serving as a crucial second messenger in cellular physiological and biochemical processes. The clinical implications of this research are substantial. The study provides a solid scientific basis for understanding how acupuncture initiates its therapeutic effects through modulation of intrinsic homeostasis, thereby avoiding the side effects of exogenous drugs or drug resistance.

The acupoint microenvironment acts as the universal initiation link for acupuncture actions, where various active factors activate receptors located on neural endings, transmitting electrical and biochemical signals to the CNS. Limitations include the fact that most reviewed studies focus only on changes in specific aspects rather than reticular network relationships and interconnections among complex substances. Future research should examine how changes in a specific substance in the microenvironment cause subsequent changes in other substances and how they affect acupuncture effects synthetically. This work establishes a foundation for future systematic studies of the complex network relationships of acupuncture points and their microenvironmental mechanisms.