Negative Feedback Loops in Chemokine Signaling and Metainflammation's Impact on Neutrophil Responses
Researchers at the Albert Einstein College of Medicine and New York University use zebrafish to study cell migration in development and inflammation.
Compared to mammals’ more limited chemokine repertoire (around 50 total in humans), teleost fish such as zebrafish, rainbow trout, and catfish possess a markedly expanded and diversified set. This diversity reflects extensive gene duplication events—both tandem and whole-genome duplications—that occurred during vertebrate evolution. These expansions likely represent adaptations to diverse aquatic pathogens and environments.
For example, zebrafish contain more than 100 chemokine genes, including over 40 CC and roughly 25 CXC family members. Rainbow trout and catfish also possess dozens of chemokines, many with lineage-specific innovations and dual roles in immunity and developmental biology. While several groups have examined chemokine-directed cell migration in zebrafish development, more recent work uses sophisticated in vivo models to understand regulatory mechanisms that ensure correct trafficking of immune and non-immune cells.
In their recent paper, de Oliveira and colleagues investigate how metainflammation—a chronic low-grade inflammatory state driven by overnutrition and high-fat diets—disrupts neutrophil behavior during tissue repair. Using a zebrafish larval model with fluorescent neutrophils and tailfin transection as an injury paradigm, the researchers induced metainflammation through a high-cholesterol diet and employed intravital confocal microscopy to track neutrophil dynamics in real time.
Neutrophil migration is a classic chemokine-mediated process. In the metainflammatory environment, the authors observed dysfunctional neutrophil responses, including exaggerated influx to sites of injury, impaired resolution of inflammation, and reverse migration from pre-activated reservoirs. These altered behaviors likely reflect disruptions in chemokine signaling, gradient sensing, or receptor desensitization caused by persistent low-grade inflammation.
In an earlier study, Holger Knaut and colleagues used the zebrafish posterior lateral line primordium—a non-immune migratory tissue—to demonstrate how the chemokine Cxcl12a (Sdf1) forms a stable gradient that guides directional migration. The gradient spans approximately 0–12 nM, closely matching the dissociation constant (Kd ˜ 3.4 nM) of its receptor Cxcr4b.
A key regulatory mechanism involves the atypical chemokine receptor Ackr3b (Cxcr7), which functions as a chemokine scavenger. When local Cxcl12a levels increase, Ackr3b expression rises and excess chemokine is removed from the environment, buffering concentrations within an optimal signaling range. Disruption of this feedback loop—through mutations that alter receptor affinity or impair Ackr3b phosphorylation—results in elevated chemokine concentrations, receptor desensitization, and loss of directional migration. These findings suggest that attractant buffering may represent a general mechanism for ensuring robust cell migration.
While the Protein Foundry catalog currently focuses on human and mouse proteins, our scientists have successfully produced chemokines from multiple additional species, including zebrafish. If your research requires a chemokine from an unusual species, a specific mutant, or a modified protein variant, contact our team and we will work with you to develop a solution.
Michael C, Cantón-Sandoval J, Feliz-Norberto M, Scharf P, de Oliveira S. Metainflammation alters neutrophil function and migration in vivo in response to tissue injury. J Leukoc Biol. 2025 Jul 9;117(7):qiaf094. PMID: 40557998.
Lau S, Feitzinger A, Venkiteswaran G, Wang J, Lewellis SW, Koplinski CA, Peterson FC, Volkman BF, Meier-Schellersheim M, Knaut H. A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration. Nat Cell Biol. 2020 Mar;22(3):266-273. PMID: 32042179;PMCID: PMC7809593.
