Neutrophils use superoxide to control bacterial infection at a distance

Phan, Quang Tien; Sipka, Tamara; Gonzalez, Catherine; Levraud, Jean‐Pierre; Lutfalla, Georges; Nguyen-Chi, Maï

doi:10.1371/journal.ppat.1007157

Cited by 71 publications

(63 citation statements)

References 64 publications

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“…Cell numbers ( mpeg1 :mCherry, ctsk :GFP, ctsk :mCherry, and cxcr3.2 :GFP) were quantified as previously described ( 58 ) with slight modifications. Using Fiji, fluorescent images were converted to greyscale and thresholded, and the area of a cell (averaged from 15 cells from three larvae) as well as the total area of cells in a selected region of interest were obtained.…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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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“…It happens mainly due to the action of NADPH oxidase complex (NOX), but can also be generated by mitochondria. After neutrophil activation, NOX acts converting molecular oxygen (O 2 ) into superoxide anion (O 2˙− ) which suffers dismutation, spontaneously or catalyzed by myeloperoxidase (MPO), generating hydrogen peroxide (H 2 O 2 ) [22,23]. In addition to ROS, neutrophils can also enhance the inducible nitric oxide synthase (NOS2) expression, which will convert O 2 to nitric oxide (NO), resulting in reactive nitrogen species (RNS).…”

Section: Actions Of Neutrophils In Infected Sitesmentioning

confidence: 99%

“…In addition to ROS, neutrophils can also enhance the inducible nitric oxide synthase (NOS2) expression, which will convert O 2 to nitric oxide (NO), resulting in reactive nitrogen species (RNS). Both ROS and RNS contribute to microbicide activity and are crucial for the defense against intracellular microorganisms [22]. Curiously, NO is supposed to be involved in the failure of neutrophil migration during sepsis, once it stimulates the internalization of CXCR2 on the neutrophil surface and reduces expression of adhesion molecules, leading to diminished leucocyte rolling and adhesion to the endothelium [12].…”

Section: Actions Of Neutrophils In Infected Sitesmentioning

confidence: 99%

Neutrophil Function Impairment Is a Host Susceptibility Factor to Bacterial Infection in Diabetes

Insuela¹,

Coutinho²,

Martins³

et al. 2020

Cells of the Immune System

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Diabetes mellitus is a highly prevalent noncommunicable disease globally. One of the main complications of diabetes is the increased susceptibility to bacterial infection. Neutrophils play a crucial role in inflammatory response against bacterial infections, once they are the first cells recruited to the sites of injury. In diabetes, there is a failure in the neutrophil functions, including migration, ROS production, phagocytosis, and bacterial killing, which are associated with the high incidence of bacterial infections. Herein, we point out pieces of evidence revealing the primary molecular mechanisms involved with impairment of neutrophil functions in diabetes, with relationship with high susceptibility to bacterial infections.

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“…Fluorescent images of whole embryos and confocal z-stacks were used for the quantification of macrophage and osteoclast numbers as previously described (23) with slight modifications. Using Fiji, fluorescent images were converted to greyscale, thresholded, and the area of a cell (averaged from 15 cells from three embryos), as well as the total area of cells in a selected region of interest, were derived.…”

Section: Cell Quantification and Statisticsmentioning

confidence: 99%

Macrophages Switch to an Osteo‐Modulatory Profile Upon RANKL Induction in a Medaka (Oryzias latipes) Osteoporosis Model

et al. 2020

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In mammals, osteoclasts differentiate from macrophages in the monocyte lineage. Although many factors driving osteoclast formation are known, the detailed processes underlying precursor recruitment, differentiation, and interaction of macrophages with other cell types involved in bone remodeling are poorly understood. Using live imaging in a transgenic medaka osteoporosis model, where ectopic osteoclasts are induced by RANKL expression, we show that a subset of macrophages is recruited to bone matrix to physically interact with bone-forming osteoblast progenitors. These macrophages subsequently differentiate into cathepsin K-(ctsk-) positive osteoclasts. One day later, other macrophages are recruited to clear dying osteoclasts from resorbed bone by phagocytosis. To better understand the molecular changes underlying these dynamic processes, we performed transcriptome profiling of activated macrophages upon RANKL induction. This revealed an upregulation of several bone-related transcripts. Besides osteoclast markers, we unexpectedly also found expression of osteoblast-promoting signals in activated macrophages, suggesting a possible non-cell autonomous role in osteogenesis. Finally, we show that macrophage differentiation into osteoclasts is dependent on inflammatory signals. Medaka deficient for TNFα or treated with the TNFα-inhibitor pentoxifylline exhibited impaired macrophage recruitment and osteoclast differentiation. These results show the involvement of inflammatory signals and the dynamics of a distinct subset of macrophages during osteoclast formation.

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Neutrophils use superoxide to control bacterial infection at a distance

Cited by 71 publications

References 64 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

Neutrophil Function Impairment Is a Host Susceptibility Factor to Bacterial Infection in Diabetes

Macrophages Switch to an Osteo‐Modulatory Profile Upon RANKL Induction in a Medaka (Oryzias latipes) Osteoporosis Model

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