What are the immunomodulatory actions of macrolides?

October 6, 2025 •

3 min read

For decades, macrolide antibiotics have been successfully used in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, showing that their effects extend beyond their antimicrobial properties. The immunomodulatory actions of macrolides offer significant therapeutic benefits in various chronic inflammatory conditions.

Quick Summary

Macrolides possess potent immunomodulatory effects, suppressing chronic inflammation by modulating cytokine production, influencing neutrophil function, and reducing mucus hypersecretion in respiratory diseases.

Key Points

Immunomodulation, not Immunosuppression: Macrolides modulate or 'reset' a hyperactive inflammatory state, unlike broad immunosuppressants that weaken the entire immune system.
Cytokine Balance: They suppress the production of pro-inflammatory cytokines (IL-8, TNF-α) and can enhance anti-inflammatory cytokines like IL-10, shifting the overall inflammatory response.
Neutrophil Regulation: Macrolides influence neutrophil behavior by reducing their recruitment, promoting their apoptosis, and inhibiting damaging oxidative bursts.
Anti-Virulence Effects: At low concentrations, macrolides impair bacterial quorum sensing and inhibit biofilm formation, reducing bacterial virulence in chronic infections.
Broad Clinical Utility: Beyond infections, macrolides are used for their immunomodulatory actions in conditions such as cystic fibrosis, COPD, bronchiectasis, and diffuse panbronchiolitis.
Focus on 14- and 15-Membered Macrolides: The immunomodulatory effects are primarily associated with 14- and 15-membered ring macrolides (e.g., erythromycin, clarithromycin, azithromycin), not the 16-membered ones.
Mitigating Resistance: The development of non-antibiotic macrolide derivatives is underway to provide immunomodulatory benefits without contributing to antimicrobial resistance.

Beyond Antimicrobial Effects: A Paradigm Shift

Macrolides, a class of antibiotics including erythromycin, azithromycin, and clarithromycin, are primarily known for inhibiting bacterial protein synthesis. However, early observations in patients with diffuse panbronchiolitis (DPB) revealed clinical improvements with long-term, low-dose macrolide therapy, even against bacteria resistant to these antibiotics. This led to the concept of macrolides having "non-antibiotic" or "immunomodulatory" effects, suggesting their ability to regulate a hyperactive inflammatory response.

Key Mechanisms of Macrolide Immunomodulation

Macrolides achieve their immunomodulatory effects through various pathways, distinct from broad immunosuppressants. These effects can vary depending on the specific macrolide, dose, and duration of treatment. For detailed information on specific mechanisms, including the modulation of inflammatory cytokines, effects on neutrophil and macrophage function, modification of bacterial virulence and biofilm formation, and regulation of airway secretion and tissue remodeling, please refer to {Link: DrOracle.ai https://www.droracle.ai/articles/134692/adverse-effects-associated-to-macrolid}.

Comparison of Immunomodulatory Actions: Specific Macrolides

The immunomodulatory effects are mainly observed with 14- and 15-membered macrolides like erythromycin, clarithromycin, and azithromycin, while 16-membered macrolides generally lack these properties. A comparison of some key macrolides shows differences in their specific effects:


Feature	Azithromycin (15-membered)	Clarithromycin (14-membered)	Erythromycin (14-membered)
Inflammatory Cytokines	Reduces pro-inflammatory cytokines like IL-8 and TNF-α; often increases anti-inflammatory IL-10.	Reduces pro-inflammatory cytokines like IL-6 and IL-8; can inhibit IL-1β.	Reduces pro-inflammatory cytokines like IL-8 and TNF-α.
Neutrophil Effects	Enhances apoptosis, inhibits oxidative burst, and reduces chemotaxis.	Can induce neutrophil extracellular traps (NETs) in some cases, with conflicting data on other effects.	Reduces neutrophil chemotaxis and oxidative burst.
Macrophage Effects	Favors anti-inflammatory M2 polarization and enhances efferocytosis.	Shifts macrophages towards an anti-inflammatory phenotype in vitro.	Modulates cytokine production in macrophages.
Anti-Virulence/Biofilm	Highly potent against P. aeruginosa quorum sensing and biofilm formation.	Inhibits P. aeruginosa quorum sensing and biofilm formation.	Inhibits P. aeruginosa virulence factors.
Mucus Regulation	Reduces mucin production (MUC5AC).	Inhibits mucin production (MUC5AC).	Inhibits mucus secretion.
Fibroblast Modulation	Shows effects on fibroblasts, reducing proliferation and fibrosis.	Inhibits MMPs and reduces pro-fibrotic markers.	Modulates fibroblast function.
Cardiac Risk	Potential for QT prolongation; evidence is inconsistent and warrants caution in at-risk patients.	Known for higher risk of QT prolongation and drug interactions.	Highest risk of QT prolongation and GI issues.

Clinical Applications in Chronic Inflammatory Diseases

Due to their immunomodulatory properties, macrolides are used in managing various chronic inflammatory conditions with significant neutrophilic involvement. Key applications include:

COPD: Long-term use can decrease exacerbations and improve patient well-being.
Cystic Fibrosis: Especially in patients with P. aeruginosa, long-term azithromycin can improve lung function and reduce exacerbations, although a recent study noted potential for resistance and altered bacterial behavior.
Bronchiectasis: Long-term macrolides can reduce sputum and exacerbations.
Asthma: Can serve as an additional treatment for specific asthma types, like those with non-eosinophilic inflammation.
Chronic Rhinosinusitis: Low-dose, long-term use can alleviate symptoms and inflammation.

Limitations and the Future of Immunomodulatory Macrolides

The main concern with long-term macrolide use is the increased risk of antimicrobial resistance. Other potential side effects include gastrointestinal issues, hearing loss, and cardiac problems.

To overcome these limitations, research is focused on developing new macrolide derivatives that retain immunomodulatory effects but lack antibacterial activity. These modified macrolides represent a promising approach for treating chronic inflammatory diseases without contributing to antibiotic resistance. For further details on macrolide mechanisms and applications, you can consult the ASM Journals article.

Conclusion

Macrolides offer therapeutic benefits beyond their antibiotic function, primarily through their significant immunomodulatory actions. They help regulate inflammation, influence immune cell activity, and modify bacterial behavior, even at sub-antimicrobial doses. These effects are particularly valuable in managing chronic inflammatory conditions like COPD and cystic fibrosis by modulating cytokine production, affecting neutrophil and macrophage function, and disrupting bacterial virulence and biofilm formation. While long-term use poses risks, the development of novel non-antibiotic macrolides is an exciting prospect for future treatments of chronic inflammation.

Frequently Asked Questions

Macrolides modulate inflammation through several mechanisms, including reducing pro-inflammatory cytokine production, interfering with signaling pathways like NF-κB, influencing the function of immune cells such as neutrophils and macrophages, and inhibiting bacterial virulence factors and biofilm formation.

Immunomodulation refers to the modification of the immune system to restore a normal, or homeostatic, state in cases of chronic, hyperactive inflammation. In contrast, immunosuppression globally dampens the immune system, potentially compromising the ability to fight infections.

Macrolides are effective at low, sub-antimicrobial doses because their immunomodulatory actions do not depend on killing bacteria. They work by altering host inflammatory responses and modifying bacterial virulence, which are effective at lower concentrations than those required for bacterial elimination.

Significant immunomodulatory effects are primarily seen with 14-membered (erythromycin, clarithromycin) and 15-membered (azithromycin) macrolides. The 16-membered macrolides generally do not possess these properties.

Risks of long-term macrolide therapy include the potential for increased antimicrobial resistance, gastrointestinal side effects (nausea, diarrhea), hearing loss, and cardiac toxicity (QT prolongation) in certain patients.

Macrolides decrease neutrophil activity by inhibiting their chemotaxis to sites of inflammation, suppressing their oxidative burst, and promoting their programmed cell death (apoptosis). This helps resolve inflammation and reduces tissue damage.

The future of immunomodulatory macrolides involves the development of novel derivatives that lack antibacterial properties. This would allow patients to benefit from the anti-inflammatory effects without risking increased antimicrobial resistance.

Macrolides help reduce the hypersecretion of mucus, a common problem in chronic inflammatory lung diseases. They do this by inhibiting the expression of mucin genes, such as MUC5AC, in airway epithelial cells.