Pathological Mechanism Of Immunoglobulin E Exacerbating Abdominal Aortic Aneurysm Disease

Background:Abdominal aortic aneurysm(AAA) is a permanent expansion of the abdominal aorta.An untreated AAA can cause the aneurysm to expand,leading to rupture and bleeding,and even death.Surgery is the main treatment for AAA,and there is still a risk of recurrence after surgery.Therefore,there is no effective treatment.Previous reports suggest that immunoglobulin E(IgE)is highly expressed in AAA tissue and serum,and is expected to become a diagnostic marker for AAAs,but there are few reports on the pathological mechanism of IgE in AAAs;and it is unclear how IgE is produced in AAA tissue.Methods and Results:Combined with previous research,IgE,as a mast cell activator,can be highly expressed in AAA patients.To investigate the function of non-vascular intrinsic cells in AAA formation,we first explored in depth how mast cells were involved in AAA development.We found that mast cells could express a metalloendopeptidase,meprin-a(Mepl A),which critically modulates the activity of proteins and inflammatory cytokines in various diseases.By investigating the functional role of Mep1 A in AAA formation and rupture,we found that Mep1 A mediated AAA formation by regulating the mast cell secretion of tumor necrosis factor alpha(TNF-α),which promoted matrix metalloproteinase(MMP)expression and apoptosis of smooth muscle cells(SMCs).Meanwhile,Mep1 A deficiency reduced AAA formation and increased the survival rate of AAA mice.Pathological analysis showed that Mepl A deletion decreased elastic lamina degradation and SMC apoptosis in AAA tissues.In vitro,TNF-α secreted by mast cells enhanced MMP2 expression in SMCs and promoted SMC apoptosis.In addition,Mep1 A inhibitor actinonin attenuated TNF-α secretion in mast cells.In order to fully interpret the function of different cells in AAA development,single-cell RNA sequencing was performed on angiotensin Ⅱ(AngⅡ)-induced AAA mouse model.By bioinformatic analyses,macrophages,B cells,T cells,fibroblast,smooth muscle cells and endothelial cells were identified.Moreover,three subtypes of macrophages were uncovered,and Trem2-A cp5" macrophages as the possible intermediate state between M1 and M2 were suggested by heterogeneity analysis.Besides,interestingly we found the involvement of fibrocytes(CD45 +CD34+)in AAA formation,and validated in mouse AAA tissue by FACS and immunofluorescence staining.More importantly,by the reconstitution of fibrocytes in AngⅡ-induced AAA model,we determined the recruitment and protective function of fibrocyte in AAA possibly by mediating extracellular matrix.Our studies reveal the heterogeneities of macrophages and the involvement of a novel type of cells,fibrocytes,in AAA.Fibrocytes may be a latent target of cell therapies for AAA considering its protective function.Conclusion:In summary,IgE can regulate inflammation by promoting Mepl A expression in mast cells,and TNF-α promotes the degradation of extracellular matrix and aggravates the occurrence of AAAs;with the help of single-cell transcriptome sequencing technology,it suggests that the source of IgE may depend on the function of B cells.Moreover,it has been found that intermediate macrophages and fibrocytes are involved in the development of AAAs.Taken together,Mep1A in mast cells and the protective function of fibrocytes may be potential targets in the interventional treatment of AAA.