Bone Marrow-Derived Mast Cells Accumulate in the Central Nervous System During Inflammation but Are Dispensable for Experimental Autoimmune Encephalomyelitis Pathogenesis

Abstract

Reports showing that W/Wv mice are protected from experimental autoimmune encephalomyelitis (EAE, a murine model of multiple sclerosis), have implicated mast cells as an essential component in disease susceptibility, but the role of mast cell trafficking has not been addressed. In this study, we have used both mast cell transplantation and genetic mutations (Cd34−/−, W/Wv, Wsh/Wsh) to investigate the role of mast cell trafficking in EAE in detail. We show, for the first time, that bone marrow-derived mast cells are actively recruited to the CNS during EAE. Unexpectedly, however, we found that EAE develops unabated in two independent genetic backgrounds in the complete absence of mast cells or bone marrow-derived mast cell reconstitution. We conclude that although mast cells do accumulate in the brain and CNS during demyelinating disease via peripheral mast cell trafficking, they are completely dispensable for development of disease.

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

“…The former study highlights that MCs accumulate in the CNS trafficking from the bone marrow during EAE but are dispensable for the development of the disease. 21 Interestingly, although in this study no difference in EAE expression between Kit W-sh/W-sh and Kit þ / þ mice was observed, an increased Ag-specific T-cell proliferation in immunized Kit W-sh/W-sh mice was reported, in line with our findings. The latter study shows that milder clinical signs of EAE in Kit W-sh/W-sh mice correlate with decreased CD8 þ T-cell activation.…”

“…It must be noted that some of the results here reported may be associated also to an alteration of histamine signalling in these MC-deficient mice, as histamine has been lately reported to reduce T cell proliferation and IFN-g production in autoreactive T cells. 54 Our data also show some discrepancy with the results obtained by other groups in the Kit W-sh/W-sh strain, showing unchanged 21 or reduced 22 EAE clinical course in these mice in comparison with WT counterpart. The former study highlights that MCs accumulate in the CNS trafficking from the bone marrow during EAE but are dispensable for the development of the disease.…”

“…19 In Kit W/W-v mice, MCs have also extra-lymphoid roles in EAE, favoring the access of neutrophils to inflamed CNS by secreting TNF in meninges. 20 In contrast to these previous works, Bennett et al 21 have recently shown that MCs are dispensable for EAE development in both Kit W/W-v and Kit W-sh/W-sh models. Conversely, Stelekati et al 22 have recently published that EAE severity is decreased in Kit W-sh/W-sh mice but is restored following MC knockin, 22 thus confirming the data obtained by Brown and colleagues in Kit W/W-v model.…”

“…21 The frequency of Th17 and Th1 cells was higher in Kit W-sh/W-sh mice at d10 post immunization. Even though the discovery that Th17 cells drove autoimmunity subverted the previous belief that Th1 cells were the most relevant pathogenic cells in EAE, it is now well accepted that both T-helper subsets participates, through distinct mechanisms, to EAE and MS pathogenesis.…”

The role of the immune system in central nervous system plasticity after acute injury

“…VEGF, the most important mitogen in the process of angiogenesis, is also secreted by infiltrating eosinophils and MCs (Horiuchi and Weller, 1997). The occurrence of MCs on the vasculature wall, their location at the branch points of vessels, their production of proangiogenic factors (such as VEGF, FGF-2, TGF-β, TNF-α, IL-8, MMPs, tryptases and chymases), suggest indeed a prominent role for MCs in the neo-angiogenetic response after ischemic damage (Bennett et al, 2009;Sayed et al, 2011;Ribatti et al, 2000;2011). MCs further contribute to neo-vascularization after ischemia through the promotion of VEGF production from non-mast cell sources (e.g.…”