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Published on: May 31, 2018
Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3
Zhiwei Ang1, Jun Zhi Er1, Nguan Soon Tan2,3
1NUS graduate School for Integrative Science and Engineering, National University of Singapore, 117543 Singapore.
Abstract:
Knockout mice studies implicate the mammalian short-chain fatty acid (SCFA) receptors, FFAR2 and FFAR3- in colitis, arthritis and asthma. However, the correlation with human biology is uncertain. Here, we detected FFAR2 and FFAR3 expression in human monocytes via immunohistochemistry. Upon treatment with acetate SCFA or FFAR2- and FFAR3-specific synthetic agonists, human monocytes displayed elevated p38 phosphorylation and attenuated C5, CCL1, CCL2, GM-CSF, IL-1α, IL-1β and ICAM-1 inflammatory cytokine expression. Acetate and FFAR2 agonist treatment also repressed Akt and ERK2 signalling. Surprisingly, mouse monocytes displayed a distinct response to acetate treatment, elevating GM-CSF, IL-1α, and IL-1β cytokine expression. This effect persisted in FFAR2/3-knockout mouse monocytes and was not reproduced by synthetic agonists, suggesting a FFAR2/3 independent mechanism in mice. Collectively, we show that SCFAs act via FFAR2/3 to modulate human monocyte inflammatory responses- a pathway that is absent in mouse monocytes.
Insights
Short-chain fatty acids (SCFAs) target FFAR2 and FFAR3 receptors in human monocytes, modulating inflammatory responses. This SCFA-FFAR2/3 pathway differs significantly in mouse monocytes, highlighting species-specific immune mechanisms.
Area of Science:
- Immunology
- Molecular Biology
- Metabolomics
Background:
- Mammalian short-chain fatty acid (SCFA) receptors FFAR2 and FFAR3 are implicated in inflammatory diseases like colitis, arthritis, and asthma in mouse models.
- The direct relevance of these SCFA receptors to human inflammatory conditions remains unclear.
Purpose of the Study:
- To investigate the role of FFAR2 and FFAR3 in human monocyte inflammatory responses.
- To compare the effects of SCFAs and their receptor agonists on human and mouse monocytes.
- To elucidate the specific signaling pathways involved in SCFA-mediated monocyte modulation.
Main Methods:
- Immunohistochemistry was used to detect FFAR2 and FFAR3 expression in human monocytes.
- Human and mouse monocytes were treated with acetate (an SCFA) and specific synthetic agonists for FFAR2 and FFAR3.
- Western blotting and cytokine analysis were performed to assess changes in protein phosphorylation (p38, Akt, ERK2) and inflammatory mediator expression (C5, CCL1, CCL2, GM-CSF, IL-1α, IL-1β, ICAM-1).
Main Results:
- Human monocytes express FFAR2 and FFAR3. Treatment with acetate or FFAR2/3 agonists modulated inflammatory responses, including elevated p38 phosphorylation and reduced expression of several key inflammatory cytokines and mediators.
- Acetate and FFAR2 agonist treatments also repressed Akt and ERK2 signaling pathways in human monocytes.
- Mouse monocytes exhibited a distinct, FFAR2/3-independent response to acetate, with increased GM-CSF, IL-1α, and IL-1β expression, even in FFAR2/3-knockout cells.
Conclusions:
- Short-chain fatty acids (SCFAs) utilize FFAR2 and FFAR3 to regulate inflammatory responses in human monocytes.
- The signaling pathways activated by SCFAs in human monocytes differ from those in mouse monocytes.
- These findings reveal a species-specific mechanism of SCFA action on monocytes, with implications for understanding and treating inflammatory diseases.
