“M1/M2” Muscularis Macrophages Are Associated with Reduction of Interstitial Cells of Cajal and Glial Cells in Achalasia

Abstract

Background and Aims Several studies showed muscularis macrophages (MMφ) are associated with GI motility disorders. The purpose of this study was to preliminary explore the association between MMφ and achalasia. Methods Tissue samples of the lower esophageal sphincter (LES) high-pressure zone were obtained from 27 achalasia patients and 10 controls. Immunohistochemistry for MMφ, interstitial cells of Cajal (ICC), neuronal nitric oxide synthase (nNOS), and glial cells were conducted. Histological characteristics were compared between groups, and correlation analysis was performed. Results Fewer ICC was found in achalasia compared with controls (P = 0.018), and the level of M1 macrophages was higher than that in controls no matter in terms of the number or the proportion of M1(P = 0.026 for M1 and 0.037 for M1/MMφ). Statistical differences were found between two groups in terms of proportion of M2 and ratio of M1 to M2 (P = 0.048 for M2/ MMφ and < 0.001 for M1/M2). For the correlation analysis, significant correlations were detected between levels of nNOS, ICC, and glial cells in patients with achalasia (P = 0.026 for nNOS and ICC, 0.001 for nNOS and glial cells, 0.019 for ICC and glial cells). There were significant correlations between M2/MMφ and levels of ICC (P = 0.019), glial cells (P = 0.004), and nNOS (P = 0.135). Conclusion Patients with achalasia had a higher level of M1/M2 ratio in LES and significant correlations were found between M2/MMφ and numbers of ICC and glial cells, which suggested that MMφ were probably associated with occurrence and development of achalasia.

The Crucial Role of the Interstitial Cells of Cajal in Neurointestinal Diseases

“…There is a consistent pattern of reduced ICC in achalasia. Often, achalasia patients show elevated levels of mast cells and M1 macrophages in the lower esophagus, which aligns significantly with the observed loss of ICC and neuronal loss [ 80 , 81 ]. Given this correlation, ICC remains an important avenue of investigation in the context of esophageal achalasia, even if its role as a nitrergic intermediary in the esophagus might be diminished.…”

Immunohistochemical characterization of interstitial cells and their relationship to motor neurons within the mouse esophagus

“…Though the roles of various populations of enteric glia are being uncovered in the colon and small intestine, little is known about these cells in the other GI regions. Previous studies in the human esophagus demonstrated the presence of S100β + cells (Hoshino et al, 2013, Qian et al, 2023. S100β is expressed by mature astrocytes within the central nervous system and is also used as a marker for enteric glial cells (Grundmann et al, 2019).…”

“…Despite these early observations, the function of ICC has not been evaluated within this region and therefore their role within the skeletal muscle is still unclear. Studies in patients with achalasia, a disease associated with disrupted peristalsis and impaired relaxation of the LES have noted a decrease in density of both ICC and nitrergic neurons (Gockel et al, 2008, Qian et al, 2023 while others have suggested that the association of ICC and nitrergic neurons is reduced in achalasic patients, rather than their density (Chen et al, 2013). PDGFRα + cells and S100β + cells are also found within the human esophagus (Qian et al, 2023).…”

“…Studies in patients with achalasia, a disease associated with disrupted peristalsis and impaired relaxation of the LES have noted a decrease in density of both ICC and nitrergic neurons (Gockel et al, 2008, Qian et al, 2023 while others have suggested that the association of ICC and nitrergic neurons is reduced in achalasic patients, rather than their density (Chen et al, 2013). PDGFRα + cells and S100β + cells are also found within the human esophagus (Qian et al, 2023). Though the morphology, distribution and function of ICC and PDGFRα + cells and their relationship to enteric neurons have been characterized throughout most of the length of the gastrointestinal (GI) tract, their distribution and morphological relationships with other cells has not been characterized in as much depth within the LES and esophagus.…”