## 4 Intraganglionic Macrophages and the Myenteric Plexus Barrier  
Early histological studies identified macrophages closely juxtaposed to nerve fibers [53] and enteric neurons [27; 54], but according to recent findings, some MPM-s are entirely located within the extracellular matrix (ECM) barrier surrounding the myenteric plexus. These macrophages were identified as a unique cell population, called intraganglionic macrophages (MPIC) (Figure 1, (16)), characterized by the expression of multiple microglial markers and a distinct ultrastructure from their extraganglionic counterparts [21; 55]. Although MPMy-s include cells whose cell bodies occur outside the ganglion, with their extensions reaching in the intraganglionic space (periganglionic macrophages), haemopoietic cells that are entirely located within the neuronal microenvironment of the ENS and express an immunological signature similar to central nervous system's (CNS), microglia (CD45, CD11b, Iba1, CSF1R) is a novel finding that further stratifies the already heterogeneous population of MPM-s [55]. It is hypothesized that MHC-II+ macrophages in the vicinity of ganglion cells phagocytose apoptotic ganglion cells [56]. This feature is reminiscent of the so-called \"scavenger\" function of microglia. Based on gene expression studies, intestinal macrophages are closest  
Figure 2: Neuron types in the ENS that have been defined by their functions, cell body morphologies, chemistries, key transmitters and projections to targets. LM longitudinal muscle, MP myenteric plexus, CM circular muscle, SM submucosal plexus, MM musculars mucosae, MUC mucosa. The numbers neuron types corresponds to the numbers in ascending interneurons; 1. Ascending interneurons; 2: Myenteric intrinsic primary afferent neurons (IPANs); 3: Intestinofugal neurons; 4: Excitatory longitudinal muscle motor neurons; 5: Inhibitory longitudinal muscle motor neurons; 6: Excitatory circular muscle motor neurons; 7: Inhibitory circular muscle motor neurons; 8: Descending interneurons (local reflex); 9: Descending interneurons (secretomotor and motility reflex); 10: Descending interneurons (migrating myoelectric complex); 11: Submu-cosal IPANs; 12: Non-cholinergic secretomotor/ vasodilator neurons; 13: Cholinergic secretomotor/vasodilator neurons; 14: Cholinergic secretomotor non-vasodilator neurons. _Created with BioRender_, modified from [PERSON], 2000 [40]. to the microglia of the CNS [57]. These include genes related to the expression profile of the two cell populations: Hnmt, Mus1, C3a1A, Dagla, Wrb, Fkbp9 or Gab1 [57]. The fractalkine receptor (CX3 CR1) is one of the few molecular markers that are uniquely specific to intestinal macrophages and microglia, but not expressed by other tissue macrophages [8]. Signs of cellular degeneration, extensive cytoplasmic vacuolization and accumulation of swollen mitochondria but no membrane-blebbing or other morphological sign of apoptosis make MP\({}_{\text{IG}}\)-s unique in terms of cellular morphology. Moreover, MP\({}_{\text{IG}}\)-s show distinct ultrastructure from extraganglionic MP\({}_{\text{My}}\)-s and have an active translational machinery and Golgi apparatus [21]. This might mean that MP\({}_{\text{My}}\)-s and MP\({}_{\text{IG}}\)-s have distinct roles in pathological conditions. A phenomena in the sciatic nerve underpins these observations, where transcriptionally unique perineurial and endoneurial macrophages are activated differentially in response to a crush injury [58]. Unlike the blood-brain-barrier (BBB) of the CNS we do not have much information about the blood-nerve barrier (BNB) protecting the ENS. While sensory dorsal root ganglia and autonomic parasympathetic and sympathetic ganglia include blood vessels, where monocytes can enter directly into the nervous tissue [59], there are no blood or lymphatic vessels inside enteric ganglia [60; 61].