Macrophage-based nanotherapeutic strategies in ulcerative colitis

Highlights

• The inflammatory signaling pathways in macrophages and ulcerative colitis (UC).

• The macrophage-based nanotherapeutic strategies for UC therapy.

• The application of advanced drug delivery systems for macrophage-based UC therapy.

Abstract

Macrophages, an important component of the innate immune response, are a key regulator of intestinal microenvironment homeostasis. These cells essentially contribute to chronic inflammatory diseases due to their strong plasticity. As is known, ulcerative colitis (UC), a chronic inflammatory disease, is closely related to immune dysfunction. A growing body of evidence suggests that the macrophage is a promising drug target for modulating the intestinal immune systems and regulating the inflammatory microenvironment, thus alleviating the inflammatory responses in UC. The macrophage-based therapy strategies for UC are still at an emerging stage. The advanced drug delivery systems can improve the macrophage-based therapy. This article will review the molecular mechanisms related to macrophage polarization and the interactions between signaling pathways that regulate the pathogenesis of UC and summarize the macrophage-based nanotherapeutic strategies in UC.

Introduction

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the digestive tract and primarily include ulcerative colitis (UC) and Crohn's disease (CD). However, unlike CD that may appear anywhere in the gastrointestinal tract in a noncontinuous manner, UC is restricted in the colon and rectum, and the main symptoms of UC include hemorrhagic diarrhea, weight loss, and abdominal cramps [[1], [2], [3]]. The major factors causing IBD involve genetic susceptibility, intestinal microflora, the external environment, and the immune response [4]. The incidence of UC is about 24.3 per 100,000 people per year in the West [3] and is clinically difficult to cure with high morbidity [5]. The global incidence of UC has increased over the past a few decades [6,7].

Currently, the main treatment strategies for UC include the use of 5-aminosalicylic acid drugs, corticosteroids, biological drugs, and immunosuppressive agents [3]. The clinical challenges are the limited efficacy of these drugs, the high price of antibody drugs, and the side effects or adverse reactions of corticosteroids and immunosuppressants. Therefore, the development of new therapeutic strategies is a pressing need, including the blockade of inflammatory signaling pathways, combination therapy, and fecal flora transplantation [[8], [9], [10], [11], [12]].

The human body's first line of defense to prevent pathogenic microorganisms from invading consists of the mucous and the skin. The mucosal immune system is tolerant towards symbiotic bacteria, but defends against pathogen invasion by initiating immune responses against the exogenous antigens. The innate immune system in the gut includes the intestinal epithelial cells (IEC) that express Toll-like receptors (TLRs) with dual-immune functions, macrophages, and dendritic cells (DCs) in the intestinal lamina propria, exerting the immunomodulatory effects on inflammatory responses. B and T cells are involved in adaptive mucosal immune responses. The effect of the complexity of the mucosal immune responses on IBD has drawn great attention [12,13]. Some drugs, such as berberine, can reconstitute the intestinal mucosal barrier function in UC by regulating the interactions among enteric glial cells–IECs–immune cells [14]. Macrophages belong to the mononuclear phagocytic system. Macrophages are an important component of the innate immune systems, with a function of maintaining tissue homeostasis by regulating apoptosis and the production of growth factors. In DSS-induced colitis mice, the number of the Mac2⁺ cells (macrophages) was much higher than that of MPO⁺ cells (neutrophil granulocytes), indicating that macrophages might weigh more on the UC pathological progression of than neutrophils [15].

Here, we will review the complex signaling pathway networks involved in the macrophages and inflammatory tissues and discuss the nanotechnology-based delivery to treat UC. The understanding of the intrinsic links between signaling pathways and macrophages is helpful to develop an efficient strategy for UC therapy (Fig. 1). Therefore, the role of macrophages in UC from the pathophysiology to macrophage-based therapies is discussed.