Macrophages in Inflammatory Bowel Disease (IBD)
Macrophages and Inflammatory bowel disease (IBD)
IBD is an inflammatory disorder of the colon and small intestine. The pathogenesis of IBD is correlated with alterations in the immunological mechanisms involved in the resolution of inflammation resulting in excessive and persistent inflammation. More recently, specific mechanisms involved in the resolution of inflammation have been identified with macrophages playing a key part in preventing an excessive immune response. Intestinal macrophages are considered to be the main players in establishing and maintaining gut homeostasis. Deregulation of intestinal macrophages, therefore, results in a loss of tolerance towards commensal bacteria and food antigens, which is believed to underlie the chronic inflammation observed in IBD.
Macrophages Polarization in IBD
Macrophages acquire specialized functional phenotypes according to the microenvironment in which they reside. The simple definition of M1 and M2 macrophage polarization has become obsolete. There is a large spectrum of macrophage activation. At least three types of macrophages are very well characterized. Macrophages described as classically activated macrophages (CAMφs) can be activated in vitro through two signals, interferon-γ (IFN-γ) and lipopolysaccharide (LPS) or other Toll-like receptors (TLR) ligand. These classically activated cells are associated with host defense, high microbicidal activity, and pro-inflammatory cytokine production. Alternatively, regulatory macrophages (Reg-Mφ) have a potent anti-inflammatory and healing function, producing high levels of grown factors, interleukin-10 (IL-10), and decreased amounts of many pro-inflammatory cytokines. These calls can be activated in response to two signals: TLR ligands like LPS, and high-density immune complexes such as adenosine, prostaglandin, among others. A third population of macrophages, called alternatively activated macrophages (AA-Mφ), can be activated in response to stimulation via IL-4 or IL-13. These cells can promote debris scavenging, tissue repair, and wound healing, besides promoting fibrosis.
Therapies of Targeting Macrophages in IBD
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Inhibition of inflammatory macrophages in the intestine by anti-inflammatory drugs. 1) Corticosteroids inhibit nuclear factor-κB (NF-κB) and activator protein 1, thereby blocking pro-inflammatory gene transcription; 2) Azathioprine and 6-mercaptopurine inhibit Ras-related C3 botulinum toxin substrate 1 (Rac1) activity, preventing JUN N-terminal kinase (JNK) phosphorylation; 3) Methotrexate reduces pro-inflammatory cytokine production only in TS+ inflammatory macrophages.
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Inhibition of inflammatory macrophages recruitment into the inflamed mucosa by Natalizumab, vedolizumab, and other compounds in development.
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Inhibition of inflammatory activation: Infliximab prevents TNF receptor (TNFR)-mediated inflammatory activation in intestinal macrophages.
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Switching intestinal inflammatory macrophages into mature pro-resolving macrophages by phosphodiesterase 4 (PDE4) inhibitors (apremilast and roflumilast).
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Macrophage-targeted nanoparticles: Mannosylated or folic acid conjugated liposomes promote differentiation of CD206+ or folate receptor-positive (FR+) inflammatory myeloid cells into pro-resolving macrophages.
Fig.1 Therapeutic strategies of IBD by targeting the macrophages.1
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Reference
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Ma, Shengjie, et al. "The role of tissue-resident macrophages in the development and treatment of inflammatory bowel disease." Frontiers in cell and developmental biology 10 (2022): 896591.
