Abstract
Immune cells sense and react to a multitude of factors including both host and microbe-derived signals. Understanding how cells translate these cues into particular cellular behaviors is a complex yet critical area of study. We have previously shown that both neutrophils and macrophages are important for controlling the fish pathogen Streptococcus iniae. Here, we report both host and bacterial determinants leading to the formation of organized macrophage aggregates as part of the host inflammatory response in a subset of infected larvae. Streptococcal capsule was a required signal for aggregate formation. Macrophage aggregation coincided with NFκB activity, and the formation of these aggregates is mediated by leukotriene B4 (LTB4) produced by neutrophils. Depletion, inhibition, or genetic deletion of leukotriene A4 hydrolase (Lta4h), which catalyzes the last step in LTB4 synthesis, resulted in the absence of macrophage aggregation. Larvae with impaired neutrophil function also had impaired macrophage aggregation; however, aggregate formation was partially rescued with the addition of exogenous LTB4. Neutrophil-specific expression of lta4h was sufficient to rescue macrophage aggregation in Lta4h-deficient larvae and increased host survival following infection. In summary, our findings highlight a novel innate immune response to infection in which specific bacterial products drive neutrophils that modulate macrophage behavior through eicosanoid signaling.
Highlights
Immune cell populations communicate to carry out coordinated responses against a broad range of insults
We have previously shown that both neutrophils and macrophages are recruited to otic vesicle infection, and simultaneous depletion of neutrophils and macrophages increased susceptibility to infection with WT S. iniae and the avirulent, capsule-deficient cpsA mutant [27]
We have shown that neutrophil derived leukotriene B4 (LTB4) modulates the macrophage inflammatory response to S. iniae infection in zebrafish larvae and that this response is dependent on the presence of both live bacteria and the production of capsule
Summary
Immune cell populations communicate to carry out coordinated responses against a broad range of insults. Immune cell populations, including neutrophils and macrophages, coordinate to carry out responses to sterile insults, for example during wound response [5,6]. Activated leukocytes release a variety of pro-inflammatory mediators to communicate with other cells, including the eicosanoid LTB4 [7,8], which is synthesized from leukotriene A4 by leukotriene A4 hydrolase (LTA4H). It is clear that in addition to their directly antimicrobial activities, activated neutrophils serve as modulators of the immune response by releasing pro-inflammatory molecules and cytokines/chemokines to recruit other immune cells to the infection site [25]. We used a zebrafish larval model and have characterized the formation of macrophage aggregates in response to infection with Streptococcus iniae. Neutrophil-specific expression of Lta4h is sufficient to rescue macrophage aggregate formation in Lta4h-deficient larvae and increases host survival
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