Mast cell-nerve interaction in the colon of Trypanosoma cruzi-infected individuals with chagasic megacolon

Abstract

Chagas disease is an infection caused by the parasite Trypanosoma cruzi that affects millions of people worldwide and is endemic in Latin America. Megacolon is the most frequent complication of the digestive chronic form and happens due to lesions of the enteric nervous system. The neuronal lesions seem to initiate in the acute phase and persist during the chronic phase, albeit the mechanisms involved in this process are still debated. Among the cells of the immune system possibly involved in this pathological process is the mast cell (MC) due to its well-known role in the bi-directional communication between the immune and nervous systems. Using ultrastructural analysis, we found an increased number of degranulated MCs in close proximity to nerve fibers in infected patients when compared with uninfected controls. We also immunostained MCs for the two pro-inflammatory molecules tryptase and chymase, the first being also important in neuronal death. The number of MCs immunostained for tryptase or chymase was increased in patients with megacolon, whereas increased tryptase staining was additionally observed in patients without megacolon. Moreover, we detected the expression of the tryptase receptor PAR2 in neurons of the enteric nervous system, which correlated to the tryptase staining results. Altogether, the data presented herein point to the participation of MCs on the denervation process that occurs in the development of T. cruzi-induced megacolon.

Biomarkers and Their Possible Functions in the Intestinal Microenvironment of Chagasic Megacolon: An Overview of the (Neuro)inflammatory Process

“…MC degranulation was found to be associated with nerve fiber network disintegration and loss of neuronal cell bodies in a coculture model between myenteric neurons and peritoneal MCs isolated from rats [146], and besides tryptase, other proinflammatory MC mediators such as IL-6 and prostaglandin 2 could induce neuronal death. The same was observed when a PAR2 agonist was used [146], corroborating what was suggested by Martins et al [34] in Chagasic megacolon.…”

“…In fact, MCs play an important role in megacolon pathophysiology. Evidence shows that the concentration of these cells is increased regardless of the affected intestine layer [13,34,138,139]; the same has been observed in a murine chronic phase model [140]. The increase in chymase-IR and tryptase-IR MCs has been shown to be correlated with decreased PGP 9.5-IR neurons in Chagasic megacolon [34].…”

“…Although most of the studies on PGP 9.5 neuronal density use the experimental models, da Silveira et al [15] and Martins et al [34] showed that patients chronically infected with megacolon presented reduced density of IR-PGP 9.5 nerve fibers in both, internal muscle layer and intestinal external muscle, as compared to nonmegacolon CD patients and noninfected.…”

“…This receptor is cleaved by tryptase and participates in hyperactivation and neuronal death, triggering chronic intestinal function changes [141]. Also, there is a proximity between MCs in active degranulation (fragmented and anaphylactic) and intestinal nerve fibers, and the subsequent neuronal death could be partially mediated by the tryptase enzyme released through MC degranulation in Chagasic megacolon, and both proteases would be involved in the maintenance of the inflammatory process in the organ [34].…”

The Colombian Strain of Trypanosoma cruzi Induces a Proinflammatory Profile, Neuronal Death, and Collagen Deposition in the Intestine of C57BL/6 Mice Both during the Acute and Early Chronic Phase

“…Substance P , a neuropeptide, has been shown to be increased in dilated portions of patients with chagasic megacolon, and this increase has been shown to be related to the induction/maintenance of intestinal inflammation and leukocyte chemotaxis, which may be related to neuronal damage [ 40 , 41 ]. In addition, proteases produced by mast cells, such as tryptase, are correlated with neuronal death in patients with chagasic megacolon, mainly by decreasing immunoreactive PAR2 neurons [ 42 ]. Our group demonstrated that type 2 bone morphogenetic proteins are correlated with neuronal destruction and with the maintenance of the intestinal proinflammatory profile in an acute-phase experimental model infected with the Y strain [ 10 ].…”