Abstract
Monocyte chemotactic protein 1-induced protein 1 (MCPIP-1) is highly expressed in activated immune cells and plays an important role in negatively regulating immune responses. However, its role in regulating neutrophil functions in the pathogenesis of inflammatory bowel disease (IBD) is still unclear. Here, we found that MCPIP-1 was markedly increased at both the transcriptional and translational levels in inflamed mucosa of IBD patients compared with healthy controls, which was mainly expressed in neutrophils. Interestingly, MG-132, a proteasome inhibitor reducing the degradation of MCPIP-1, further facilitated neutrophils to express MCPIP-1 in vitro. Importantly, MCPIP-1 markedly downregulated the production of ROS, MPO, and proinflammatory cytokines (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α, interleukin-8, and interferon-γ) and suppressed the migration of IBD neutrophils. Consistently, the same functional changes were observed in neutrophils from mice with myeloid-targeted overexpression of MCPIP-1 as MG-132 did. Altogether, these findings suggest that MCPIP-1 plays a negative role in regulating neutrophil activities through suppressing the production of ROS, MPO, and proinflammatory cytokines and inhibiting the migration. MG-132 may partially modulate the function of neutrophils via the induction of MCPIP-1. Therefore, targeting MCPIP-1 or exogenous supplementation of MG-132 may provide a therapeutic approach in the treatment of IBD.
Highlights
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease that affects the gastrointestinal tract
We first determined the expression of Monocyte chemotactic protein 1-induced protein 1 (MCPIP-1) in the intestinal mucosa of patients with IBD and heathy donors by qRT-PCR and found that the expression of MCPIP-1 was higher in the intestinal mucosa of patients with IBD compared to heathy donors (Supplementary Figure 2(a))
We found that MCPIP-1 was mainly expressed in CD4+ T cells, monocytes, macrophages, and neutrophils from peripheral blood (n = 10) and intestinal mucosa (n = 9 ), especially in neutrophils (Supplementary Figures 2(b) and (c))
Summary
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease that affects the gastrointestinal tract. As a feature of dysregulated intestinal immune responses in IBD, increasing numbers of neutrophils are observed to accumulate in the affected mucosa and serve as an indispensable effector in the pathogenesis [7]. As the first line of host defense against the invasion of invading microbes, neutrophils migrate to inflammatory sites under inflammatory conditions [9] They eliminate invading microorganisms through phagocytosis, the release of antibacterial peptides (e.g., cathepsin, defensin, and calprotectin) from granules, the production of reactive oxygen species (ROS) and myeloperoxidase (MPO), and the formation of neutrophil extracellular traps (NETs) [10,11,12]. Extravasation of neutrophils from peripheral blood to inflamed intestinal mucosa is related to the disease activity of IBD patients [15], and excessive production of ROS may cause tissue damage [16]. Neutrophils regulate intestinal homeostasis and are involved in the pathogenesis of IBD in several ways, the underlying mechanisms whereby neutrophils regulate intestinal mucosal immune responses in IBD are still not clear
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