Figure 1.

The mechanism of neuroimmune regulation in HAEC. Macrophages are the main source of bone morphogenetic protein 2 (BMP2), which stimulate intestinal neurons to regulate gastrointestinal motility. In turn, the development and reproduction of Macrophages are controlled by colony stimulating factor (CSF1) expressed by intestinal neurons. Adrenergic nerve fibers regulate muscular macrophages to participate in the protection of neurons by acting on β2AR. Cholinergic nerve fibers regulate the conversion of macrophages from M1 to M2 to inhibit the development of inflammation by acting on a7nAchR, which increases the ratio of Treg/Th17 in intestinal mucosa. M1 macrophages release TNF-α that makes cells of Cajal lose the c-kit phenotype and causes intestinal motility disorder. In the aganglionic segment of colon in patient with HSCR, mast cells release neurotrophic factors (NTFs) to promote the proliferation and hypertrophy of nerve fibers. SP from peptidergic neurons promotes mast cells degranulation, resulting in releasing of pro-inflammatory mediators such as TNF-α, IL-1β and trypsin, inducing neuronal injury. GDNF from EGCs can significantly inhibit mast cell degranulation and reduce inflammation. A sharp arrow indicates functional promotion, while a flat arrow indicates inhibition.