Frontline Science: Antagonism between regular and atypical Cxcr3 receptors regulates macrophage migration during infection and injury in zebrafish

Sommer, Frida; Torraca, Vincenzo; Kamel, Sarah M.; Lombardi, Amber; Meijer, Annemarie H.

doi:10.1002/jlb.2hi0119-006r

Cited by 29 publications

(36 citation statements)

References 74 publications

(229 reference statements)

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“…Importantly, Cxcr3.2 is not required for macrophage migration or recruitment to clear inflammatory insult (Movies S9-S11 and ref. 36). Hence, we speculate that this receptor marks a distinct subset of macrophages, which differentiates into osteoclasts at mineralized bone matrix.…”

Section: The Chemokine Receptor Cxcr32 Marks a Subset Of Macrophagesmentioning

confidence: 84%

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model

Phan

Tan

Liu

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only a few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify druggable pathways, we generated a medaka (Oryzias latipes) osteoporosis model, where inducible expression of receptor-activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts and excessive bone resorption, which can be assessed by live imaging. Here we show that upon Rankl induction, osteoblast progenitors up-regulate expression of the chemokine ligand Cxcl9l. Ectopic expression of Cxcl9l recruits mpeg1-positive macrophages to bone matrix and triggers their differentiation into osteoclasts. We also demonstrate that the chemokine receptor Cxcr3.2 is expressed in a distinct subset of macrophages in the aorta-gonad-mesonephros (AGM). Live imaging revealed that upon Rankl induction, Cxcr3.2-positive macrophages get activated, migrate to bone matrix, and differentiate into osteoclasts. Importantly, mutations in cxcr3.2 prevent macrophage recruitment and osteoclast differentiation. Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis.

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Section: The Chemokine Receptor Cxcr32 Marks a Subset Of Macrophagesmentioning

confidence: 84%

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model

Phan

Tan

Liu

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, a novel chemokine axis has been implicated in the recruitment of macrophages to wounds. The Cxcr3/Cxcl11 receptor-ligand pair was shown to contribute to macrophage migration toward tail wounds using knockouts of the respective receptors in zebrafish (122). The CXCR3 receptor exists as three paralogs in zebrafish (Cxcr3.1, Cxcr3.2, and Cxcr3.3), whereby Cxcr3.2 and Cxcr3.3 antagonistically function during macrophage recruitment.…”

Section: Neutrophil Retrograde Chemotaxis Helps Resolve Neutrophilic mentioning

confidence: 99%

“…The CXCR3 receptor exists as three paralogs in zebrafish (Cxcr3.1, Cxcr3.2, and Cxcr3.3), whereby Cxcr3.2 and Cxcr3.3 antagonistically function during macrophage recruitment. As both receptors share the same ligand, Cxcr3.2 promotes macrophage migration toward the wound, whereas Cxcr3.3 negatively regulates Cxcr3.2 function by acting as a scavenger receptor for Cxcl11 ( Figure 4B) (122).…”

Section: Neutrophil Retrograde Chemotaxis Helps Resolve Neutrophilic mentioning

confidence: 99%

The Diverse Roles of Phagocytes During Bacterial and Fungal Infections and Sterile Inflammation: Lessons From Zebrafish

Linnerz

Hall

2020

Front. Immunol.

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The immediate and natural reaction to both infectious challenges and sterile insults (wounds, tissue trauma or crystal deposition) is an acute inflammatory response. This inflammatory response is mediated by activation of the innate immune system largely comprising professional phagocytes (neutrophils and macrophages). Zebrafish (danio rerio) larvae possess many advantages as a model organism, including their genetic tractability and highly conserved innate immune system. Exploiting these attributes and the live imaging potential of optically transparent zebrafish larvae has greatly contributed to our understanding of how neutrophils and macrophages orchestrate the initiation and resolution phases of inflammatory responses. Numerous bacterial and fungal infection models have been successfully established using zebrafish as an animal model and studies investigating neutrophil and macrophage behavior to sterile insults have also provided unique insights. In this review we highlight how examining the larval zebrafish response to specific bacterial and fungal pathogens has uncovered cellular and molecular mechanisms behind a variety of phagocyte responses, from those that protect the host to those that are detrimental. We also describe how modeling sterile inflammation in larval zebrafish has provided an opportunity to dissect signaling pathways that control the recruitment, and fate, of phagocytes at inflammatory sites. Finally, we briefly discuss some current limitations, and opportunities to improve, the zebrafish model system for studying phagocyte biology.

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“…The small size and transparency of their larvae are useful characteristics for the screening and imaging of transgenic reporter lines ( Meijer and Spaink, 2011 ). Zebrafish larvae are a popular model for studying functions involved in wound repair ( Renshaw et al, 2006 ; Niethammer et al, 2009 ; Xie et al, 2019 ; Bernut et al, 2020 ; Katikaneni et al, 2020 ; Sommer et al, 2020b ). The availability of mutants in TLR signaling genes tlr2 and myd88 make it possible to study their roles in leukocyte migratory behavior upon tail wounding in zebrafish ( Henry et al, 2013 ; van der Vaart et al, 2013 ; Hu et al, 2019 ; Xie et al, 2019 ; Sommer et al, 2020b ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Function of TLR2 and MyD88 in the Regulation of Leukocyte Cell Migration Behavior During Wounding in Zebrafish Larvae

Steijn

et al. 2021

Front. Cell Dev. Biol.

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Toll-like receptor (TLR) signaling via myeloid differentiation factor 88 protein (MyD88) has been indicated to be involved in the response to wounding. It remains unknown whether the putative role of MyD88 in wounding responses is due to a control of leukocyte cell migration. The aim of this study was to explore in vivo whether TLR2 and MyD88 are involved in modulating neutrophil and macrophage cell migration behavior upon zebrafish larval tail wounding. Live cell imaging of tail-wounded larvae was performed in tlr2 and myd88 mutants and their corresponding wild type siblings. In order to visualize cell migration following tissue damage, we constructed double transgenic lines with fluorescent markers for macrophages and neutrophils in all mutant and sibling zebrafish lines. Three days post fertilization (dpf), tail-wounded larvae were studied using confocal laser scanning microscopy (CLSM) to quantify the number of recruited cells at the wounding area. We found that in both tlr2–/– and myd88–/– groups the recruited neutrophil and macrophage numbers are decreased compared to their wild type sibling controls. Through analyses of neutrophil and macrophage migration patterns, we demonstrated that both tlr2 and myd88 control the migration direction of distant neutrophils upon wounding. Furthermore, in both the tlr2 and the myd88 mutants, macrophages migrated more slowly toward the wound edge. Taken together, our findings show that tlr2 and myd88 are involved in responses to tail wounding by regulating the behavior and speed of leukocyte migration in vivo.

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Frontline Science: Antagonism between regular and atypical Cxcr3 receptors regulates macrophage migration during infection and injury in zebrafish

Cited by 29 publications

References 74 publications

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model

The Diverse Roles of Phagocytes During Bacterial and Fungal Infections and Sterile Inflammation: Lessons From Zebrafish

A Novel Function of TLR2 and MyD88 in the Regulation of Leukocyte Cell Migration Behavior During Wounding in Zebrafish Larvae

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