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Ginger in Your Diet and Neutrophil Function

Ginger, everyone’s favorite fiery fragrant spice, does more than just add punch and taste to your food: it turns out that [6]-gingerol, a component of ginger, has an unexpected effect on neutrophils. In new research,  food ingredients step into the spotlights as scientists dig deeper into the role of sensory active TRP (transient receptor potential) channels in non-sensory tissues and explore how [6]-gingerol, a common TRPV1 agonist impacts the cellular immune responses of primary human neutrophils.

Neutrophils and the Multifaceted TRPV1 Channel

In this work, the researchers have focused specifically on the TRPV1 channel. Previously known for their roles in sensory and thermal perception, TRP channels are now gaining attention for their roles in non-sensory tissues. TRPV1, a member of this family, has been found to play roles beyond mere sensory functions. For example, the agonist nonivamide has shown potential in fat loss and serotonin regulation. However, the function of TRPV1 in human neutrophils remains relatively unexplored.

Neutrophils, major players of the immune system, are no strangers to complexities. They possess an arsenal of defense mechanisms including phagocytosis, degranulation, and generation of reactive oxygen species (ROS). Yet, their interaction with TRPV1 has largely been a grey area. Past studies have suggested that constituents from food or medicinal plants could affect neutrophil functions, such as ROS production, but have failed to identify the active compounds involved.

The study here hypothesizes that a nutritionally relevant concentration of [6]-gingerol can alter the general functions of human neutrophils. Researchers sought to uncover whether this concentration could affect cellular immune responses, including ROS production and the secretion of chemokine CXCL8.

TRPV1 Channels Make More Than a Cameo

Using live cell flow cytometry, the researchers not only probed the existence of TRPV1 channels in neutrophils. The team used flow cytometry to assess TRPV1 channel expression on the surface of primary human neutrophils, cells that are a critical part of our immune system. They isolated these cells and marked them with CD15, a surface protein often used as a cellular ID for neutrophils. These tagged cells were then stained with an antibody targeting TRPV1’s first extracellular loop to observe any interaction.

This particular antibody, Anti-Human TRPV1 (extracellular)-FITC antibody (#ACC-334-F), which targets only the extracellular portion of the TRPV1 channel and is directly conjugated to fluorescein isothiocyanate (FITC), is only available from Alomone Labs.

The results were illuminating (Figure 1). The fluorescence intensity for FITC was clearly distinguishable when neutrophils were stained with the TRPV1-specific antibody as opposed to the control, confirming TRPV1 does indeed appear on the surface of neutrophils, offering a new avenue for understanding these cells’ behavior.

To ensure that this wasn’t just a fluke, the study extended the experiment to neutrophils from four individual donors. The fluorescence signals were comparable across the board, reinforcing the notion that TRPV1 surface expression is a general characteristic of human neutrophils, rather than an anomaly.

TRPV1 Surface Expression on Neutrophils

Figure 1. The TRPV1 channel is expressed on the surface of human neutrophils. Flow cytometry of isolated human neutrophils, stained either with a TRPV1 specific antibody B) or the corresponding isotype control A), both conjugated to FITC. Cells were additionally stained for CD15. Numbers in the plots indicate either values for forward and side scatter or mean fluorescence intensity of the staining. C) Histogram overlay of the stains for TRPV1 and isotype control. D) Histogram overlay of the stains for TRPV1 of four individual donors. Figure and legend from Andersen, G., et al (2023)  Molecular Nutrition & Food Research, 67(4), 2200434.

Ginger vs Neutrophil Activity

An experiment using Fura-2, a Ca2+-sensitive dye, tracked the effect of [6]-gingerol on intracellular Ca2+ concentrations in neutrophils. After a 2-hour incubation period with 50 nM [6]-gingerol, a noticeable rise in calcium levels was observed. On average, there was an 18.4% increase in calcium concentrations compared to the effect of the ionophore ionomycin, commonly used as a control.

Expanding on this, researchers next questioned whether this activation of TRPV1 by [6]-gingerol led to changes in the gene expression of TRPV1 itself. After a similar 2-hour incubation period, the levels of TRPV1 transcripts and proteins remained stable. In addition, common cytokine and chemokine genes largely remained unaffected, apart from a few exceptions like IL6 and IL24.

Concentration Matters 

The team observed significant changes in protein expression on neutrophils after a 2-hour incubation with 50 nM of [6]-gingerol. This led to an increase in the expression of key markers such as FPR1, CD11b, and CD66b, which are involved in neutrophil activation and response. Also, when stimulated with fMLF – a potent neutrophil activator – the cells showed increased secretion of the chemokine CXCL8. Interestingly, these effects were specific to a narrow concentration range of fMLF, which suggests a nuanced relationship between [6]-gingerol and neutrophil function.

One interesting observation is that the 2-hour incubation with [6]-gingerol did not directly increase ROS production. This suggests that [6]-gingerol doesn’t initiate ROS production but enhances the cell’s responsiveness to other activating stimuli, perhaps preparing the cell for more robust action when required. Whether this is a form of “priming” is yet to be confirmed.

The study raises an intriguing point about concentration-dependent effects. Higher concentrations of fMLF led to receptor desensitization, negating the effect of [6]-gingerol. This supports the theory that higher concentrations of TRPV1 ligands may inhibit neutrophil functions, whereas lower concentrations like 50 nM might augment them. This brings into question what the optimal concentration range might be for potential therapeutic applications.

What Lies Ahead

The work here suggests that common food ingredients with sensory properties, such as ginger, can have a measurable effect on cellular activity in immune cells. This action occurs through the TRPV1 channel and, given that TRP channels are widely expressed in these cells, the results stress the need for further evaluation of how everyday concentrations of food ingredients could impact biological activity.

While the findings affirm the functional role of TRPV1 in human neutrophils, a lot of questions remain. The study only investigated the effects at a specific concentration of [6]-gingerol, leaving the door open for exploring the impact of different concentrations. Moreover, the focus was mainly on short-term responses, necessitating a deeper dive into long-term effects. Nonetheless, the study validates the potential of [6]-gingerol to act as a modulator of neutrophil functions at concentrations achievable through dietary intake. By shedding light on how everyday food components can modulate cellular immune responses, the study offers an appetizing avenue for future research.

Antibodies

Pharmacological Tools

  • LASSBio-1135 (#L-190) (CHEMBL466188) – A blocker of TRPV1 channels and antagonist of TNF-α receptors
  • Arvanil (#A-335) (N-Vanillylarachidonamide) – An agonist of TRPV1 channels and a ligand of CB1 receptors