Microscopic view of the intestine with immune cells and lupus butterfly pattern

Gut Check: How Your Intestinal Macrophages Could Be Key to Understanding Lupus

Rhea Morgan in Health & Wellness July 2025 • 4 min read.

"Unlocking the secrets of mucosal immunity and its connection to systemic lupus erythematosus."

Monocytes, the body's first responders, play a crucial role in initiating immune responses against pathogens and managing inflammation. Once activated, these monocytes migrate to various tissue sites, transforming into macrophages that orchestrate both innate and adaptive immune reactions.

Within the gut, mucosal macrophages are vital. They typically produce anti-inflammatory cytokines, but disruptions in this process have been increasingly linked to autoimmune diseases like systemic lupus erythematosus (SLE).

This article delves into the function of human macrophages within the intestinal environment, focusing on their role in maintaining immune homeostasis and their potential involvement in the development of SLE. Further, the significance of sex differences in intestinal macrophages and their contribution to the physiology and pathogenesis of SLE will be highlighted.

What Role Do Intestinal Macrophages Play?

Microscopic view of the intestine with immune cells and lupus butterfly pattern

The gut's mucosal barrier, composed of the epithelium and lamina propria, is essential for maintaining overall health. Tight junctions between epithelial cells carefully regulate what enters the body. This barrier protects against harmful pathogens while allowing trace amounts of bacterial products to cross over, which is necessary to maintain systemic immune balance.

Intestinal macrophages, key players in this complex environment, possess unique characteristics. Unlike macrophages found elsewhere in the body, these cells have limited proliferative capacity and a shorter lifespan. These macrophages are replenished by a steady influx of monocytes from the bloodstream. Adding another layer, these monocytes differ from the body's resident macrophages.

CD14 and CD16 Expression: Human peripheral monocytes are categorized into subsets based on the presence of CD14 and CD16 markers.
Classical Monocytes (CD14++CD16-): These are activated by Toll-like receptor (TLR) ligands like lipopolysaccharides (LPS). Once activated, they differentiate into macrophages or dendritic cells (DCs), releasing cytokines and migrating to tissues.
Intermediate Monocytes (CD14++CD16+): Research indicates these are associated with cardiovascular diseases.
Non-Classical Monocytes (CD14+CD16++): These monocytes primarily produce pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 when stimulated by TLR agonists. It is thought that they could be associated with autoimmune conditions.

Monocytes act as processors of DCs, and these are also vital for adaptive immune responses. Macrophages facilitate intestinal homeostasis and immunity by engulfing antigens and maintaining tolerance to both self and harmless antigens. Unlike typical M1 or M2 macrophages, intestinal macrophages perform their roles through a variety of activities that dictate immune system results.

The Future of Lupus Research

Macrophage-mediated tolerance and the prevention of pro-inflammatory responses to TLR ligands are essential for mucosal immunity. Altered TLR-mediated innate immune responses in intestinal macrophages may significantly contribute to SLE pathogenesis. Further studies could investigate how sex hormones affect intestinal macrophage function, gut mucosal immunity, and microbial translocation, thus improving SLE therapy.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

Everything You Need To Know

What is the primary function of intestinal macrophages within the gut?

Intestinal macrophages, located within the gut's mucosal barrier, are key in maintaining immune homeostasis. They uniquely balance tolerance to self and harmless antigens while defending against pathogens. Unlike typical M1 or M2 macrophages, these intestinal macrophages carry out diverse activities to influence immune system outcomes, preventing excessive inflammation and supporting overall gut health. They also facilitate intestinal homeostasis and immunity by engulfing antigens and maintaining tolerance.

How do disruptions in the function of intestinal macrophages relate to systemic lupus erythematosus (SLE)?

Disruptions in the normal function of intestinal macrophages, particularly in their ability to produce anti-inflammatory cytokines, have been increasingly linked to autoimmune diseases like systemic lupus erythematosus (SLE). Altered TLR-mediated innate immune responses in intestinal macrophages may significantly contribute to SLE pathogenesis. This suggests that the delicate balance maintained by these macrophages is crucial in preventing the development or progression of SLE.

What are the different subsets of human peripheral monocytes, and how are they categorized?

Human peripheral monocytes are categorized into subsets based on the presence of CD14 and CD16 markers. There are three main subsets: Classical Monocytes (CD14++CD16-), which are activated by TLR ligands like lipopolysaccharides (LPS) and differentiate into macrophages or dendritic cells (DCs); Intermediate Monocytes (CD14++CD16+), which research indicates are associated with cardiovascular diseases; and Non-Classical Monocytes (CD14+CD16++), which primarily produce pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 when stimulated by TLR agonists. These different subsets play distinct roles in immune responses and inflammation.

What role do Toll-like receptors (TLRs) play in the function of intestinal macrophages, and what is the implication for systemic lupus erythematosus (SLE)?

Toll-like receptors (TLRs) on intestinal macrophages are essential for recognizing pathogens and initiating appropriate immune responses. Classical Monocytes (CD14++CD16-) are activated by TLR ligands like lipopolysaccharides (LPS). However, altered TLR-mediated innate immune responses in these intestinal macrophages may significantly contribute to SLE pathogenesis. The prevention of pro-inflammatory responses to TLR ligands are essential for mucosal immunity. This suggests that imbalances in TLR signaling within these macrophages could lead to the development or exacerbation of SLE.

How might future research into intestinal macrophages lead to improved therapies for systemic lupus erythematosus (SLE)?

Future research could investigate how sex hormones affect intestinal macrophage function, gut mucosal immunity, and microbial translocation, thus improving SLE therapy. Macrophage-mediated tolerance and the prevention of pro-inflammatory responses to TLR ligands are essential for mucosal immunity. Further studies into the function of intestinal macrophages, particularly focusing on how sex hormones influence their behavior and how they interact with the gut microbiota, could identify new therapeutic targets for SLE. By understanding these mechanisms, researchers may be able to develop interventions that restore immune homeostasis in the gut and prevent the systemic inflammation characteristic of SLE.