Dysregulated inflammatory response to urogynecologic meshes in women with diabetes and its implications

Abstract

BackgroundDiabetes is an independent risk factor for mesh complications in women undergoing mesh-augmented surgical repairs of stress urinary incontinence and/or pelvic organ prolapse. The underlying mechanism remains unclear. ObjectivesTo define the diabetes-associated alterations in the host inflammatory response to mesh and correlate them with perioperative glucose managements. Study DesignDeidentified demographics and medical records of patients who underwent mesh removal and participated in a Mesh Biorepository study were reviewed (n=200). In patients with diagnosed diabetes (n=25), blood glucose management prior to initial mesh implantation, and before and after mesh removal was assessed by blood glucose and HbA1c levels. Age- and BMI-matched tissue samples excised from patients with or without diabetes were examined. Transcriptomic profiles of immune cell markers, immune mediators, key inflammatory regulators, cell senescence, and epigenetic enzymes were determined by multiplex transcriptomic assays (NanoString). Ratio of apoptotic cells to CD68+ macrophages were examined with immunofluorescence. Protein profile of 12 molecules involved in apoptotic cell clearance were assayed with a multiplex protein assay (Luminex). ResultsDemographic and clinical characteristics, including duration between mesh implantation and removal, reason for removal, and type of mesh, etc., were comparable between patients with and without diabetes, except for 11.6% higher BMI in the former (p<0.001). In patients with diabetes, suboptimal management of blood glucose following mesh implantation was observed, with 59% of the patients having loosely or poorly controlled glucose before and after the mesh removal. Ongoing chronic inflammatory response was observed in the excised mesh-tissue complexes in both groups, while markers for M2 macrophages (mannose receptor C-type 1 [Mrc1]) and helper T cells (CD4 molecule [Cd4]) were increasingly expressed in the diabetic vs. nondiabetic groups (p=0.023, 0.047, respectively). Furthermore, the gene expression of proinflammatory C-C motif chemokine ligand 24 (Ccl24) and C-C motif chemokine ligand 24 (Ccl13) were upregulated by 1.5- and 1.8-fold (p=0.035, 0.027, respectively), while that of interleukin 1 alpha (Il1a) was paradoxically downregulated by 2.2-fold (p=0.037) in the diabetic vs. nondiabetic group. Interestingly, strong positive correlations were found between the expression of Ccl13, SET domain bifurcated histone lysine methyltransferase 2 (Setdb2), and M2 macrophage markers, as well as between the expression of Il1a, activator protein-1 transcription factor subunit (Fosl1), and dendritic cell markers, suggesting the involvement of macrophages and dendritic cells in the diabetes-dysregulated proinflammatory response. Supportively, apoptotic cell clearance, which is an important function of macrophages, appeared to be impaired in the diabetic group with a significantly increased protein level of calreticulin (CALR), an ‘eat-me’ signal on apoptotic cell surface (p=0.03), along with an increase of AXL receptor tyrosine kinase (AXL) (p=0.03), which mediates apoptotic cell clearance. ConclusionsDiabetes was associated with altered long-term inflammatory response in complicated mesh implantation, particularly involving innate immune cell dysfunction. Suboptimal blood glycemic control following mesh implantation may contribute to this immune dysregulation, necessitating further mechanistic studies.