PHAGOCYTE/PLAY: Issue 2

Issue 2: Beyond Keto: The Real Science of Insulin Resistance

How ketones condition Macrophages

Macrophages are programmable. In broad strokes, M1 macrophages amplify inflammation and microbe-killing, while M2 macrophages resolve inflammation and repair tissue.***

Ketone bodies—especially β-hydroxybutyrate (BHB)—nudge that balance by changing signals, enzymes, and even epigenetics inside these cells.

***This is a very broad generalization and not the way I like to think of macrophages but it’s a common way to talk about them without going into the complexities of macrophage profiles. For an overview of macrophages, you can watch my presentation at IHMC for a lay audience: https://youtu.be/-CQqfkrae00?si=Lkuqlyi18NamHaLg

1) Inflammasome brake: BHB → ↓ NLRP3

BHB directly blocks the NLRP3 inflammasome, the molecular “match” that ignites IL-1β and IL-18 release in M1 states. Mechanistically, BHB prevents K⁺ efflux and ASC speck formation, damping the cascade without needing AMPK, ROS, or autophagy pathways. In mice, raising BHB levels reduced NLRP3-driven inflammatory disease.

Why it matters: turning down NLRP3 lowers a key amplifier of sterile inflammation (metabolic syndrome, neuroinflammation, gout), biasing macrophages away from an M1 phenotype. Additional work extends this effect to neutrophils and brain inflammation models.

2) Receptor signal: BHB → HCAR2 (GPR109A)

BHB is also a ligand for HCAR2 (GPR109A), the same receptor hit by niacin and dimethyl fumarate. Activating HCAR2 on monocytes/macrophages promotes an anti-inflammatory program and, in neuroinflammatory models, was necessary for the protective effect of ketogenic states. Recent structural/biased-agonism studies strengthen the case that HCAR2 signaling in macrophages is a druggable anti-inflammatory axis.

3) Epigenetic tune-up: BHB as an HDAC inhibitor

Inside cells, BHB acts as an endogenous class I HDAC inhibitor, increasing histone acetylation and stress-resilience gene expression. That epigenetic shift supports a tilt away from pro-inflammatory transcriptional programs—one reason fasting/ketosis often correlates with a calmer innate immune tone.

4) Polarization programs: toward M2, away from M1

Beyond blocking NLRP3, BHB promotes M2-like features via STAT6-dependent signaling in colitis models (more repair, less tissue damage). Newer work shows BHB can post-translationally modify key proteins (lysine β-hydroxybutyrylation), including STAT1, blunting its LPS-driven M1 transcription—another route away from inflammatory polarization.

Functional upshot: in spinal cord injury and other contexts, ketogenic metabolism correlated with more M2 markers, less inflammatory damage, and better tissue recovery—consistent with the mechanistic signals above. (Animal/early translational evidence; human confirmation needed.)

5) Important nuance (read this*)**

Context matters. Substrate mix, glucose availability, species, and tissue niche shape outcomes. One livestock study showed low glucose + BHB could increase pro-inflammatory signaling via GPR109A/NF-κB in yak alveolar macrophages—useful as a reminder that biology isn’t one-note. PubMed
Endogenous vs exogenous. Nutritional ketosis changes many levers at once (substrates, hormones, redox, gut signals). A ketone drink spikes BHB for hours but doesn’t recreate the full milieu; immune effects may therefore differ in size or direction. (Inference built on mechanistic and clinical contrasts from this issue.)
Dose & duration. Many immune effects were shown at millimolar BHB and over short windows; long-term human data on macrophage polarization with therapeutic ketosis are limited.

Ketones don’t just fuel cells; they condition them. In macrophages, BHB dampens a core inflammatory switch (NLRP3), signals through HCAR2 to reduce inflammatory tone, and rewrites gene programs via HDAC inhibition and β-hydroxybutyrylation—changes that, together, bias toward M2-like, pro-resolution behavior. It’s elegant biology with clinical promise, worth watching, but not yet a license for supplement hype.

References

Youm YH, et al. “BHB blocks NLRP3 inflammasome.” Nat Med. 2015.
Rahman M, et al. “HCAR2 activation in monocytes/macrophages.” Sci Rep. 2022
Taggart AK, et al. “GPR109A in inflammation.” Nat Med. 2005.
Shimazu T, et al. “BHB as an endogenous HDAC inhibitor.” Science. 2013.
5. Xie Z, et al. “Lysine β-hydroxybutyrylation and metabolic signals.” Cell Metab. 2016.
Rahman M, et al. “BHB modulates macrophage phenotype.” J Neuroinflammation. 2014.
Tan M, et al. “Ketogenic metabolism and macrophage M2 polarization.” Front Immunol. 2022.
Wang T, et al. “Low-glucose + BHB induce macrophage inflammatory signals in yak lung models.” Front Vet Sci. 2022.