Tollip Orchestrates Macrophage Polarization to Alleviate Intestinal Mucosal Inflammation

Abstract

Background and Aims Macrophage polarization regulation is a promising strategy for treating inflammatory bowel disease (IBD). Tollip is an important negative regulator of Toll-like receptor (TLR)-mediated innate immunity with downregulated expression in the colon tissues of patients with IBD. This study aims to regulate the expression of Tollip to affect macrophage polarization. Methods A molecular, targeted immunotherapy method was developed by linking mannose-modified trimethyl chitosan (MTC) with Tollip-expressing plasmids via ionic cross-linking, forming MTC-Tollip nanoparticles with a targeting function. MTC-Tollip selectively targeted mouse intestinal macrophages to regulate the polarization of macrophages for mucosal repair. Results Orally administered MTC-Tollip significantly elevated Tollip expression in intestinal tissue. Compared with MTC-negative control (NC)-treated mice in which colitis was induced with dextran sodium sulfate (DSS), the MTC-Tollip NP-treated mice exhibited decreased body weight loss and colon shortening, lower proinflammatory cytokine expression in colon tissues, and greater mucosal barrier integrity. MTC-Tollip treatment decreased TNF-α and iNOS expression but increased CD206 and Arg-1 expression in colon tissue. Tollip overexpression in mouse peritoneal macrophages inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine production and promoted interleukin (IL-4)-induced M2 expression. The progression of peritoneal macrophages extracted from Tollip −/− mice confirmed the effect of Tollip on macrophage polarization. Western blots showed that Tollip overexpression attenuated the upregulation of TLR pathway-associated targets in M1 macrophages. Conclusions MTC-NPs can be intelligent carriers in immunotherapy. The modulation of Tollip expression in macrophages may be a novel treatment approach for IBD.

Multiple CAR-T cell therapy for acute B-cell lymphoblastic leukemia after hematopoietic stem cell transplantation: A case report

“…In contrast, approximately 80% of patients with ALL after CD19 CAR-T cell therapy had CR after CD22 CAR-T cell therapy, which was not different from patients who did not receive CD19 CAR-T cell therapy (20, 39). Although we did not detect the mean fluorescence intensity (MFI) of CD19 and CD22, CD19 and CD22 in Figure 2A were analyzed by Image-Pro Plus software through the method of Liu X et al (40). The mean density of CD19 (0.32 ± 0.01) was higher than that of CD22 (0.21 ± 0.00), indicating that the expression intensity of CD19 was still very high.…”

“…Although we did not detect the mean fluorescence intensity (MFI) of CD19 and CD22, CD19 and CD22 in Figure 2A were analyzed by Image-Pro Plus software through the method of Liu X et al. ( 40 ). The mean density of CD19 (0.32 ± 0.01) was higher than that of CD22 (0.21 ± 0.00), indicating that the expression intensity of CD19 was still very high.…”

CD73 blockade alleviates intestinal inflammatory responses by regulating macrophage differentiation in ulcerative colitis

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Advanced Nanomedicine: Redefining Therapeutic Paradigms for Inflammatory Bowel Disease

“…It has been well evidenced that M1-to-M2 macrophage polarization can block the inflammatory response and mitigate IBD. [111,112] Up till now, macrophage regulation has become one of the main directions in IBD treatment, which involves the macrophagetargeting drug delivery systems, macrophage-associated signaling pathways, and regulation of macrophage phenotypes. [56,57] Recently, a variety of biomimetic nanomedicines have shown great potential in reprogramming macrophages to the antiinflammatory phenotype in the treatment of IBD.…”