The GLP-1 receptor agonist Exendin-4 switches from anti-inflammatory to pro-inflammatory signaling in monocytes after burn injury, driven by a G protein switch from Gαs to Gαi.
Pro-inflammatory reversalExendin-4 reduced TNF-α in healthy monocytes but increased it in burn monocytes — a complete reversal of its expected anti-inflammatory effect
What the researchers found
Exendin-4 reduced TNF-α secretion from sham (healthy) monocytes but unexpectedly increased it from burn monocytes. This reversal was caused by a switch in GLP-1 receptor signaling: burn monocytes showed reduced Gαs expression and increased Gαi expression compared to sham cells. Blocking Gαi signaling with pertussis toxin reversed the pro-inflammatory effect. In burn monocytes, Exendin-4 failed to stimulate cAMP production (the normal anti-inflammatory pathway) and instead activated ERK1/2 and NF-κB pro-inflammatory pathways.
Why it matters
GLP-1-based therapies are increasingly used in critical care to manage hyperglycemia. This study reveals a potentially dangerous paradox: in burn-injured patients, these drugs might worsen inflammation rather than help. Understanding this signaling switch is essential for safe use of GLP-1 receptor agonists in critically ill and trauma patients, a population where blood sugar management is crucial.
How the study worked
Splenic monocytes were isolated from sham and burn-injured BALB/c mice 24 hours after injury. Cells were treated with Exendin-4 alone or with Gαi inhibitor (pertussis toxin) or PKA blocker (H89). Researchers measured cell viability (CCK-8), cytokine levels (ELISA), cAMP levels, PKA activity, NF-κB activation, ERK1/2 phosphorylation (Western blot), and GLP-1R downstream protein expression (immunofluorescence and Western blot).
What this study cannot tell us
This is a mouse study using ex vivo monocyte cultures, so the findings may not directly apply to human patients. The burn model represents a specific type of injury, and the G protein switch may not occur in all inflammatory conditions. Only splenic monocytes were studied — other immune cell types may respond differently. The study used Exendin-4 specifically; other GLP-1 receptor agonists may behave differently.
How to read the evidence
This is a preclinical mechanistic study in a mouse model with detailed molecular analysis. While the signaling pathway was thoroughly characterized with multiple experimental approaches, the findings are from animal cells in an ex vivo system and have not been validated in humans.
When this study was published
Published in 2018, this study provided an early warning about GLP-1 receptor agonist behavior in trauma that remains relevant as these drugs become more widely used in diverse patient populations.
The bigger picture
This study challenges the assumption that GLP-1 receptor agonists are universally anti-inflammatory. The concept of injury-induced G protein switching in immune cells has broader implications for how we understand peptide drug behavior in critical illness. As GLP-1 drugs like semaglutide and liraglutide become widely prescribed, understanding how their effects change in different physiological states — especially trauma, surgery, and critical care — becomes increasingly important for patient safety.
Questions still open
- Does this Gαs-to-Gαi switch occur with other GLP-1 receptor agonists like semaglutide or liraglutide in burn or trauma settings?
- Is this signaling switch reversible, and if so, what determines when it switches back?
- Should GLP-1 receptor agonist use be reconsidered or modified in critically ill burn patients?
Common questions
What is Exendin-4 and how is it related to GLP-1 drugs?
Should burn patients stop taking GLP-1 drugs?
Read the original research
Proinflammatory switch from Gαs to Gαi signaling by Glucagon-like peptide-1 receptor in murine splenic monocyte following burn injury.
Inflammation research : official journal of the European Histamine Research Society ... [et al.], 67(2), 157-168
Citation
Zhang, Qing-Hong; Hao, Ji-Wei; Li, Guang-Lei; Ji, Xiao-Jing; Yao, Xu-Dong; Dong, Ning; Yao, Yong-Ming. (2018). Proinflammatory switch from Gαs to Gαi signaling by Glucagon-like peptide-1 receptor in murine splenic monocyte following burn injury.. Inflammation research : official journal of the European Histamine Research Society ... [et al.], 67(2), 157-168. https://doi.org/10.1007/s00011-017-1104-9