Macrophages in Inflammatory Bowel Disease (IBD)

Macrophages in Inflammatory Bowel Disease (IBD)

Macrophage Biology in IBD Pathogenic Role of Macrophages in IBD Therapies of Targeting Macrophages in IBD Related Services Related Products Scientific Resources

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.

Macrophage Biology in IBD

Factors	Impact on Macrophage Phenotype
Cytokine Milieu	The cytokine-rich environment of the inflamed gut skews macrophage polarization. High levels of IFN-γ and LPS favor M1 polarization. IL-10 and TGF-β secretion by regulatory T cells (Tregs) and epithelial cells promote M2 polarization.
Hypoxia	Hypoxia-inducible factors (HIFs) modulate macrophage metabolism and function, favoring a pro-inflammatory phenotype under certain conditions.
Dietary and Microbial Metabolites	Short-chain fatty acids (SCFAs) such as butyrate, derived from microbial fermentation, promote M2-like anti-inflammatory activity. Metabolites like succinate can drive M1 polarization by activating pro-inflammatory pathways.
Extracellular Matrix Components	Changes in the extracellular matrix, such as increased deposition of fibronectin or hyaluronan during inflammation, provide signals that can exacerbate M1 polarization and perpetuate inflammation.

In IBD, an imbalance between M1 and M2 macrophages is frequently observed, and overexpression of M1 macrophages exacerbates disease pathology. The intestinal microenvironment has a profound effect on macrophage behavior, shaping macrophage phenotype and function through a range of signals from the extracellular matrix, stromal cells, cytokines, and metabolites. Key factors include:

Macrophages do not act in isolation. Their interactions with intestinal epithelial cells and the gut microbiota are central to maintaining intestinal homeostasis and mediating inflammatory responses in IBD.

Macrophage-Epithelial Cell Interactions

Macrophages support epithelial integrity by secreting growth factors, which promote epithelial cell proliferation and repair.
Macrophages respond to epithelial cell-derived alarmins (e.g., IL-33, HMGB1) by amplifying inflammatory signaling.
Intestinal macrophages, located beneath the epithelium, sample luminal antigens and convey signals to both epithelial and immune cells.

Macrophage-Microbiota Interactions

Macrophages detect microbial components through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs).
Microbiota-derived metabolites influence macrophage metabolism, directly impacting their inflammatory or anti-inflammatory functions.
A healthy microbiota promotes tolerogenic macrophage phenotypes, while dysbiosis skews macrophages toward a pro-inflammatory state.
Macrophages shape the composition of the gut microbiota through the secretion of antimicrobial peptides and cytokines.

Pathogenic Role of Macrophages in IBD

Macrophage-Driven Cytokine Storms

Tumor Necrosis Factor-Alpha (TNF-α)

Activating NF-κB pathways in epithelial cells and immune cells.
Promoting recruitment of neutrophils and lymphocytes to the inflamed mucosa.
Inducing apoptosis in intestinal epithelial cells, exacerbating mucosal damage.

Interleukin-1 Beta (IL-1β)

Drives the differentiation of naïve T cells into pro-inflammatory Th17 subsets.
Enhances vascular permeability, worsening local tissue edema.
Potentiates fibroblast activation, laying the groundwork for fibrosis.

Interleukin-6 (IL-6)

Inducing the survival and proliferation of effector T cells, particularly Th17 and Tfh cells.
Disrupting mucosal homeostasis through STAT3-mediated epithelial cell dysregulation.
Supporting the generation of acute-phase reactants, further escalating systemic inflammatory responses.

Contribution to Intestinal Barrier Dysfunction

Secretion of Barrier-Disrupting Cytokines

TNF-α and IL-1β induce disassembly of tight junction proteins, such as occludin and claudin, increasing epithelial permeability.
IL-6 disrupts epithelial regeneration by impairing stem cell niches in the crypts.

Impaired Clearance of Apoptotic Cells

Macrophages exhibit defective efferocytosis in IBD, resulting in the accumulation of apoptotic epithelial cells. This unregulated cell death fosters breaches in the barrier and exposes underlying tissues to luminal antigens.

Stimulation of Mucosal Immune Responses

Increased epithelial permeability allows the translocation of microbial products, such as lipopolysaccharides (LPS), into the lamina propria. These products engage macrophage Toll-like receptors (TLRs), perpetuating a vicious cycle of immune activation and tissue injury.

Therapies of Targeting Macrophages in IBD

The pathogenesis of IBD is multifactorial, involving genetic, environmental, microbial, and immunological contributors. Among these, macrophages have emerged as pivotal players in driving intestinal inflammation, presenting a unique therapeutic target for addressing the complex mechanisms underlying IBD.

Strategies	Specific Programs
Modulating Macrophage Polarization	Small molecules: Agents such as Tofacitinib (a JAK inhibitor) reduce M1-driven cytokine signaling, indirectly promoting M2-like activity. Cytokine therapies: IL-10 and IL-4 administration has shown promise in preclinical models for promoting anti-inflammatory macrophage phenotypes.
Targeting Macrophage Recruitment and Trafficking	Inhibition of inflammatory macrophage recruitment into the inflamed mucosa. Integrin blockers: Therapies targeting integrins reduce macrophage trafficking by interfering with leukocyte adhesion molecules.
Macrophage-specific Nanomedicine	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.
Inhibiting Macrophage Cytokine Production	Corticosteroids inhibit nuclear factor-κB (NF-κB) and activator protein 1, thereby blocking pro-inflammatory gene transcription. Azathioprine and 6-mercaptopurine inhibit Ras-related C3 botulinum toxin substrate 1 (Rac1) activity, preventing JUN N-terminal kinase (JNK) phosphorylation. Methotrexate reduces pro-inflammatory cytokine production only in TS+ inflammatory macrophages.
Enhancing Macrophage-mediated Resolution of Inflammation	Specialized pro-resolving mediators (SPMs): These lipid mediators (e.g., resolvins, protectins) enhance macrophage phagocytosis of apoptotic cells and debris, accelerating tissue healing. Macrophage adoptive transfer: Infusion of ex vivo-modified anti-inflammatory macrophages is being investigated as a potential therapeutic modality.

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Cat.No	Product Name	Product Type
MTS-0922-JF10	Human Macrophages, Alveolar	Human Macrophages
MTS-0922-JF99	Human M0 Macrophages, 1.5 x 10^6	Human M0 Macrophages
MTS-0922-JF52	C57/129 Mouse Macrophages, Bone Marrow	C57/129 Mouse Macrophages
MTS-0922-JF7	Human M2 Macrophages, Peripheral Blood, 10 x 10^6	Human M2 Macrophages
MTS-1022-JF1	B129 Mouse Bone Marrow Monocytes, 1 x 10^7 cells	Immune cells
MTS-1022-JF10	Human PB CD14+ Monocytes (Age: 23), 5 x 10^7 cells	Immune cells
MTS-1022-JF5	CD1 Mouse Bone Marrow Monocytes, 1 x 10^7 cells	Immune cells
MTS-1123-HM11	Monocyte To Macrophage Differentiation Associated Protein (MMA) ELISA Kit, Colorimetric	ELISA Kit
MTS-1123-HM9	Macrophage Expressed Gene 1 (MPEG1) ELISA Kit, Colorimetric	ELISA Kit
MTS-1123-HM15	Macrophage Chemokine Ligand 19 (CCL19) ELISA Kit, qPCR	ELISA Kit
MTS-1123-HM50	Macrophage Migration Inhibitory Factor (MIF) Competition ELISA Kit	ELISA Kit
MTS-1122-YF49	MacroCargo™ Human Monocyte-derived Macrophages (MDMs) with Chemo drugs (Nanoparticle System, Oligomannose-coated liposome)	MacroCargo
MTS-1122-YF19	MacroCargo™ Human PBMC-derived Macrophages with Chemo drugs (Nanoparticle System, PLGA)	MacroCargo
MTS-1122-YF49	MacroCargo™ Human Monocyte-derived Macrophages (MDMs) with Chemo drugs (Nanoparticle System, Oligomannose-coated liposome)	MacroCargo
MTS-0124-LX2	IFN-α Lentiviral Particle for Macrophage Engineering	Virus Particles
MTS-0124-LX3	IL-1β Lentiviral Particle for Macrophage Engineering	Virus Particles