Fasting Reprograms Resident Tissue Macrophages

Macrophages are immune cells that detect, engulf, and destroy pathogens, dead cells, and debris, playing a key role in immunity and tissue repair. Resident tissue macrophages (RTMs) are specialized immune cells that reside in different organs, adapting to their local environment to maintain local immune defense, tissue homeostasis, and repair. There are around eight major types of RTMs. Each type of RTMs plays a crucial role in sustaining organ function and immune balance. Unlike circulating monocytes that differentiate into macrophages upon tissue entry, RTMs originate mainly from yolk sac progenitors during embryonic development and are maintained by self-renewal.

Guardians of Tissue Homeostasis

Homeostasis is the process by which the body maintains a stable internal environment despite external changes, ensuring optimal function.

Fasting promotes homeostasis by reprogramming metabolism, reducing inflammation, and enhancing cellular repair. Fasting reprograms resident macrophages, enhancing immunity and reducing inflammation. Fasting profoundly influences resident tissue macrophages by shifting their metabolism from glucose reliance to fatty acid oxidation and ketone body utilization, reducing inflammation and enhancing tissue repair.

Fasting and Microglia

Fasting profoundly impacts microglia, the resident immune cells of the brain, by shifting their metabolism from glucose dependence to fatty acid oxidation and ketone body utilization. This metabolic reprogramming enhances autophagy, reducing the accumulation of toxic proteins linked to neurodegenerative diseases like Alzheimer’s and Parkinson’s.

Fasting also suppresses pro-inflammatory cytokines while increasing anti-inflammatory mediators, promoting a neuroprotective environment. Additionally, fasting enhances synaptic pruning and plasticity, improving cognitive function and memory. These changes make fasting a promising strategy for reducing neuroinflammation, protecting against cognitive decline, and maintaining brain health.

Fasting and Alveolar Macrophages

Fasting influences alveolar macrophages, the resident immune cells of the lungs, by shifting their metabolism from glucose dependence to fatty acid oxidation and ketone body utilization. This metabolic adaptation reduces the production of pro-inflammatory cytokines while enhancing anti-inflammatory responses, leading to better lung homeostasis.

Fasting also promotes autophagy, which helps alveolar macrophages clear damaged cells, inhaled particles, and pathogens more efficiently. These effects contribute to improved respiratory immunity, reduced lung inflammation, and enhanced defense against infections, making fasting a potential strategy for maintaining lung health and preventing chronic respiratory diseases.

Fasting and Kupffer Cells

Fasting significantly affects Kupffer cells, the resident macrophages of the liver, by shifting their metabolism to fatty acid oxidation and ketone body utilization. This metabolic shift reduces the secretion of pro-inflammatory cytokines and enhances anti-inflammatory mediators, promoting liver homeostasis.

Fasting also triggers autophagy, helping Kupffer cells clear toxins, damaged organelles, and lipid deposits, thereby protecting against non-alcoholic fatty liver disease (NAFLD). Additionally, it enhances Kupffer cells’ role in iron metabolism, bilirubin clearance, and immune surveillance, making fasting a powerful tool for maintaining liver health and metabolic balance.

Fasting and Cardiac Macrophages

Fasting influences cardiac macrophages, the resident immune cells of the heart, by shifting their metabolism from glucose reliance to fatty acid oxidation and ketone body utilization. This metabolic adaptation reduces the production of pro-inflammatory cytokines and enhances anti-inflammatory responses, protecting against chronic inflammation and fibrosis.

Fasting also promotes autophagy, allowing cardiac macrophages to clear damaged cells and oxidative stress byproducts, which helps maintain heart tissue integrity. Additionally, fasting improves mitochondrial efficiency, supporting cardiac repair, electrical conduction, and overall cardiovascular function, making it a potential strategy for enhancing heart health.

Fasting and Osteoclasts

Fasting affects osteoclasts, the bone-resorbing macrophages, by shifting their metabolism to fatty acid oxidation and ketone body utilization.

While fasting promotes autophagy and reduces inflammation, prolonged fasting can increase osteoclast activity, leading to enhanced bone resorption and potential bone density loss. However, controlled fasting, such as intermittent fasting, may help balance bone remodeling by reducing chronic inflammation and improving osteoblast-osteoclast interactions, supporting overall bone health.

Fasting and Splenic Macrophages

Fasting affects splenic macrophages, which play a key role in red blood cell recycling and immune defense, by shifting their metabolism to fatty acid oxidation and ketone body utilization. This metabolic change reduces pro-inflammatory cytokine production while enhancing anti-inflammatory responses, supporting a balanced immune environment. Fasting also promotes autophagy, improving splenic macrophages’ ability to clear senescent red blood cells and pathogens efficiently. These adaptations contribute to enhanced immune surveillance, reduced oxidative stress, and improved spleen function.

Fasting and Langerhans Cells

Fasting influences Langerhans cells, the antigen-presenting macrophages of the skin, by shifting their metabolism to fatty acid oxidation and ketone body utilization. This metabolic adaptation reduces pro-inflammatory cytokine production while enhancing immune tolerance, helping maintain skin homeostasis.

Fasting also promotes autophagy, improving Langerhans cells' ability to clear damaged proteins and regulate immune responses to pathogens and allergens. These effects contribute to stronger skin immunity, reduced inflammation, and improved barrier function.

Fasting and Intestinal Macrophages

Recent research has deepened our understanding of how fasting influences intestinal macrophages and overall gut health.

Fasting alters macrophage metabolism, reducing their reliance on glucose and shifting to fatty acid oxidation. This change affects their immune function and inflammatory responses.

Studies suggest that intermittent fasting, including time-restricted feeding and alternate-day fasting, reduces gut inflammation by lowering inflammatory markers and improving microbiota composition.

Fasting enhances the communication between intestinal macrophages and type 3 innate lymphoid cells, increasing the secretion of interleukin-22 (IL-22), a key cytokine involved in gut barrier integrity, immune regulation, and tissue repair. IL-22 is primarily secreted by innate lymphoid cells and intestinal macrophages, and its levels increase during fasting, promoting mucosal healing and antimicrobial defense. This cytokine plays a crucial role in reducing gut inflammation, supporting epithelial regeneration, and maintaining a balanced gut microbiome. By boosting IL-22 levels, fasting helps protect against gut permeability issues and enhance immune tolerance.

These findings highlight the potential of fasting as a strategy to regulate gut immunity and overall digestive health.