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Immunity｜Miao Jing’s team at the Beijing Institute for Brain Research develops a fluorescent sensor for chemokine CXCL10 to map spatiotemporal immune signaling

Release time：2025-08-28 11:33:39

The chemokine CXCL10 is one of the key signaling molecules mediating cell migration during development and immune responses. It specifically recruits effector cells for directed migration and regulates their activation, proliferation, and survival, exhibiting remarkable functional complexity and specificity¹–³. Dysregulated chemokine signaling is closely associated with brain tumors and autoimmune diseases, underscoring its important clinical relevance⁴,⁵. Studies have shown that chemokine function depends not only on steady-state concentration but also on spatiotemporal dynamics, such as the steepness of spatial gradients and temporal fluctuations⁶. These “spatiotemporal coding” mechanisms are finely tuned by molecular processes such as receptor internalization and proteolytic modification⁷–¹⁰. However, there has been a lack of tools to track CXCL10 dynamics in vivo with high spatiotemporal resolution, limiting deeper insights into its functional mechanisms.

On August 15, 2025, Miao Jing’s laboratory at the Beijing Institute for Brain Research published a study in Immunity titled “Spatiotemporal dynamics of CXCL10 encode contextual immune information revealed by the genetically encoded fluorescent sensor.” This work overcame existing technological barriers by designing and developing a novel genetically encoded fluorescent sensor, GRAB-LoX3-1.0, based on the principle of G protein–coupled receptor activation (GRAB). The sensor enables high-resolution in vivo tracking of CXCL10 and reveals how CXCL10 conveys contextual information through “spatiotemporal coding” under different immune states. This study provides a powerful tool and theoretical framework for dissecting the complex functions of chemokines.

https://doi.org/10.1016/j.immuni.2025.07.005

1. Design and optimization of a genetically encoded fluorescent sensor for detecting chemokine CXCL10

Based on the modular principle of GRAB sensors, the researchers constructed a sensing module recognizing ligands and a fluorescent reporting module. By screening combinations of the CXCL10 receptor CXCR3 with conformation-sensitive fluorescent protein cpGFP from diverse natural and viral receptor sources, they selected CXCR3–cpGFP as the initial scaffold. Through iterative screening of key sites in the transmembrane region, the receptor–fluorophore interface, and within the fluorescent protein itself, they developed the sensor LoX3-1.0, which showed ~200% response amplitude to CXCR3 agonists.

Figure 1. Design strategy and iterative screening for the CXCL10 fluorescent sensor.

2. Monitoring heterogeneous CXCL10 dynamics in the brain under different inflammatory states using LoX3-1.0

Given the excellent in vitro performance of LoX3-1.0, the researchers further applied it to resolve dynamic changes of CXCL10 in the brain under distinct immune states. Continuous low-dose or prior high-dose LPS stimulation drove the brain immune milieu into specific “tolerant” or “primed” states, respectively, which in turn produced strikingly different response patterns upon subsequent challenges. Compared with the naïve group, which exhibited delayed onset and moderate responses following initial LPS exposure, the recurrent group—upon receiving a second high-dose LPS challenge—showed markedly earlier onset and stronger responses, but with a rapid decay within ~12 hours, resulting in shorter duration. In contrast, the tolerant group displayed almost no significant signal elevation upon high-dose LPS stimulation. These findings demonstrate that LoX3-1.0 can capture multidimensional CXCL10 dynamics in vivo that are tightly matched to the underlying immune state.

Figure 2. State-dependent CXCL10 dynamics in brain inflammation.

3. Revealing vascular perivascular immune state–driven CXCL10 gradients and their evolution using LoX3-1.0

From a spatial perspective, the researchers systematically analyzed the spatiotemporal dynamics of CXCL10 gradients in the brain during inflammation. The results showed that CXCL10 exhibited a vessel-centered gradient distribution pattern that continuously evolved with immune progression. Quantitative analysis revealed that in the early phase of inflammation, chemokines formed shallow and weak gradients over a limited range. During the mid-phase, the gradient peak increased substantially, the spatial coverage expanded, and the slope steepened. By the late phase, although the peak and slope of the gradient remained relatively high, the overall signal-to-noise ratio markedly declined. Importantly, even when the absolute concentration and coverage of CXCL10 changed in later immune stages, the slope of the spatial gradient remained stable, suggesting that this dimension of signaling may be critical for guiding cell migration. The spatial dynamics of CXCL10 in vivo thus provide rich contextual information for fine-tuning downstream cellular behavior. Altogether, LoX3-1.0 enabled precise mapping of chemokine spatial distributions within intact tissue, laying the groundwork for functional studies.

Figure 3. Micrometer-scale gradients and evolution of CXCL10 during brain inflammation.

4. Conclusion
Chemokines are central signals orchestrating cell migration and immune homeostasis, yet how they encode information through dynamic patterns has remained unclear. In this study, the genetically encoded fluorescent sensor GRAB-LoX3-1.0 was developed, featuring high signal-to-noise ratio, nanomolar affinity, millisecond temporal resolution, and submicron spatial resolution. For the first time, high-precision visualization of CXCL10 dynamics was achieved. Using LoX3-1.0, the researchers systematically uncovered the spatiotemporal patterns and multidimensional coding features of CXCL10 under distinct immune states, and validated its dynamic distribution in both skin injury and brain inflammation models. This work provides a powerful new tool and theoretical foundation for decoding chemokine functions and immune information transfer in inflammatory contexts. An artistic illustration accompanying the study abstractly depicts chemokines (moonlight) guiding cells (boatmen) toward their destinations, drawn by Zhixuan Sun from Tsinghua University.

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Immunity｜Miao Jing’s team at the Beijing Institute for Brain Research develops a fluorescent sensor for chemokine CXCL10 to map spatiotemporal immune signaling

1. Design and optimization of a genetically encoded fluorescent sensor for detecting chemokine CXCL10

2. Monitoring heterogeneous CXCL10 dynamics in the brain under different inflammatory states using LoX3-1.0

3. Revealing vascular perivascular immune state–driven CXCL10 gradients and their evolution using LoX3-1.0

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Immunity｜Miao Jing’s team at the Beijing Institute for Brain Research develops a fluorescent sensor for chemokine CXCL10 to map spatiotemporal immune signaling

1. Design and optimization of a genetically encoded fluorescent sensor for detecting chemokine CXCL10

2. Monitoring heterogeneous CXCL10 dynamics in the brain under different inflammatory states using LoX3-1.0

3. Revealing vascular perivascular immune state–driven CXCL10 gradients and their evolution using LoX3-1.0

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