Age-related dysregulation of CXCL9/10 in monocytes is linked to impaired innate immune responses in a mouse model of Staphylococcus aureus osteomyelitis

Lin, Yihuang; Yang, Mankai; Cheng, Chubin; Wu, Jichang; Yu, Bin; Zhang, **anrong

doi:10.1007/s00018-024-05311-2

Age-related dysregulation of CXCL9/10 in monocytes is linked to impaired innate immune responses in a mouse model of Staphylococcus aureus osteomyelitis

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Published: 13 July 2024

Volume 81, article number 300, (2024)
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Age-related dysregulation of CXCL9/10 in monocytes is linked to impaired innate immune responses in a mouse model of Staphylococcus aureus osteomyelitis

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Yihuang Lin^1,2,3^na1,
Mankai Yang^1,2^na1,
Chubin Cheng^1,2,
Jichang Wu^1,2,
Bin Yu^1,2 &
…
**anrong Zhang ORCID: orcid.org/0000-0002-0992-5013^1,2

Abstract

Background

Age-associated impairments in innate immunity are believed to be a causative factor responsible for severe pathogenesis of Staphylococcus aureus (S. aureus) infection in the bone tissue. However, the basis for age-associated decline in innate immune response upon S. aureus infection remains poorly understood.

Results

Our transcriptional data (GEO: GSE166522) from a mouse model of S. aureus osteomyelitis show up-regulated CXCL9 and CXCL10 (CXCL9/10), which is further confirmed in vitro and in vivo by the present study. Notably, monocytes are a main source for CXCL9/10 production in bone marrow upon S. aureus challenge, but this response declines in middle-aged mice. Interestingly, conditional medium of bone marrow monocytes from middle-aged mice has a strikingly decreased effect on bactericidal functions of neutrophils and macrophages compares with that from young mice. We further show that activation of CXCL9/10-CXCR3 axis between monocytes and macrophages/neutrophils promotes the bactericidal function of the cells, whereas blocking the axis impairs such function. Importantly, treatment with either exogenous CXCL9 or CXCL10 in a middle-aged mice model enhances, while pharmacological inhibition of CXCR3 in young mice model impairs, bacterial clearance and bone marrow structure.

Conclusions

These findings demonstrate that bone marrow monocytes act as a critical promotor of innate immune response via the CXLCL9/10-CXCR3 axis upon S. aureus infection, and that the increased susceptibility to S. aureus infection in skeleton in an aged host may be largely attributable to the declined induction of CXCR9/10 in monocytes.

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Background

Staphylococcus aureus (S. aureus) is the main causative pathogen of osteomyelitis in long bones and vertebrae [Full size image

CXCL9/10 can be expressed and secreted by a variety of cells, including myeloid cells and T cells [24, 25]. As T-cell cytokines in S. aureus-infected bone exhibit a late activation pattern typically observed between 7 and 14 days post-infection [26, 27], we did not assess the expression of CXCL9/10 in T cells by day 3 post-infection in our study. To evaluate cellular sources of CXCL9/10 in bone marrow myeloid cells during S. aureus infection, we isolated monocytes, bone marrow-derived macrophages (BMDMs) and neutrophils, which are main components of S. aureus abscess [28], from the femoral bone marrow in 8-week-old mice and 10-month-old mice, and challenged them with various MOI of S. aureus. The purity of isolated monocytes, neutrophils, and BMDMs from bone marrow were determined by flow cytometry with surface markers before further experiments. There was an average purity of 88.7% for CD11b⁺Ly6C⁺ monocytes, 88.37% for CD11b⁺Ly6G⁺ neutrophils and 94.93% for CD11b⁺F4/80⁺ macrophages, respectively (Fig. S4a-S4f), confirming the reliability of our cell isolations. In response to S. aureus challenge, monocytes represented the major cell type that had strikingly increased mRNA expression of both CXCL9 and CXCL10 in response to S. aureus challenge, while expression of CXCL9/10 was only partially increased or unchanged in macrophages and neutrophils upon S. aureus challenge (Fig. 3i and j). Notably, S. aureus failed to activate the expression of CXCL9/10 in all three types of cells from 10-month-old mice (Fig. 3i and j), consistent with the reduced protein levels of CXCL9/10 in the S. aureus-infected femurs from 10-month-old mice. In sum, our data suggest that monocytes might be the major cellular sources of CXCL9/10 upon S. aureus infection in the bone marrow, and that the local CXCL9/10 production response might be reduced in monocytes from middle-aged mice after S. aureus infection.

Monocyte-derived CXCL9/10 is critical for the bactericidal function of neutrophils and macrophages from bone marrow

Recent studies have indicated critical roles of monocytes in immune escape, immune tolerance and wound repair during S. aureus infection [29,30,31]. Therefore, before evaluation of the function of CXCL9/10, we evaluated whether the effect of monocytes from young mice on innate immune responses might be different from that from middle-aged mice upon S. aureus infection. We isolated bone marrow monocytes from 8-week-old and 10-month-old mice, and challenged them with S. aureus or vehicle for 12 h, before we collected and filtered the conditioned medium (CM) for bacterial killing assay in neutrophils or macrophages. Flow cytometry analysis showed that predominant neutrophils isolated from Percoll were CMFDA⁺PI⁻ viable cells and 30 min of S. aureus challenge had no much effect on the percentage of CMFDA⁺PI⁻ neutrophils (Fig. S5a and S5b). In addition, there was a notable increase in DHE-labelled ROS levels compared with non-infected neutrophils (Fig. S5c and S5d), indicating reactiveness of the isolated neutrophils to S. aureus infection. We found that neutrophils treated with CM of S. aureus-challenged monocytes from 8-week-old mice (CM-8 W Mono-S. aureus) had significantly fewer extracellular and intracellular bacterial colonies compared with those treated with CM of vehicle-treated monocytes from 8-week-old mice (CM-8 W Mono-Vehicle) (Fig. 4a-c). Noticeably, neutrophils treated with CM of S. aureus-challenged monocytes from 10-month-old mice (CM-10 M Mono-S. aureus) had similar extracellular and intracellular bacterial loadings with those treated with CM of vehicle-treated monocytes from 10-month-old mice (CM-10 M Mono-Vehicle), and had a strikingly higher bacterial loading compared with those treated with CM-8 W Mono-S. aureus (Fig. 4a-c). Similar to the observations in neutrophils, a significant decreased bacterial loading was observed in macrophages treated with CM-8 W Mono-S. aureus compared with those treated with CM-8 W Mono-Vehicle. Meanwhile, CM-10 M Mono-S. aureus-treated bone marrow-derived macrophages (BMDMs) had a similar bacterial loading with CM-10 M Mono-Vehicle-treated ones, but had a strikingly higher bacterial expansion compared with CM-8 W Mono-S. aureus-treated ones (Fig. 4d and e). These results suggest that S. aureus-challenged monocytes from young mice may improve the bactericidal function of neutrophils and macrophages, but those from middle-aged mice may not.

The chemotaxis function of CXCL9/10 is known as its action on its cognate receptor C-X-C motif chemokine receptor 3 (CXCR3) in immune cells such as macrophages, neutrophils and other immune cells [32]. Moreover, recent literature has demonstrated the protective role of CXCR3 blockade against virus infection [33, 34]. These prompted us to determine whether the presence of CXCL9/10 upon S. aureus infection might be functionally relevant to the bactericidal function of innate immune cells. We pretreated neutrophils in vitro with recombinant mouse CXCL9, CXCL10, and a combination of them to measure the bacterial killing capacity of neutrophils. Interestingly, we found that the number of extracellular bacterial colonies was significantly decreased in the wells treated by CXCL9 or CXCL10 (Fig. 5a and b). Meanwhile, we also observed a significant decline in intracellular bacterial colonies in the neutrophils treated by CXCL9 or CXCL10 (Fig. 5a and c). Whereas, the combination of CXCL9 and CXCL10 treatment didn’t further reduce either extracellular or intracellular bacterial load of neutrophils compared with treatment with either CXCL9 or CXCL10 (Fig. 5a-c). In addition, there was a significant decrease in the number of bacterial colonies in the BMDMs treated by either CXCL9 or CXCL10, and a combination of CXCL9 and CXCL10 further reduced bacterial load in BMDMs (Fig. 5d and e).

We next investigated whether the elevated expression of CXCL9/10 in monocytes in response to S. aureus infection might be responsible for the elevated bactericidal activity of neutrophils and macrophages. We isolated primary monocytes from 8-week-old mice bone marrow, and treated them with siRNA fragments targeting CXCL9 or CXCL10 or control ones for 48 h before S. aureus infection. The knock-down efficiency of siRNA fragments was evaluated by qPCR, and si-CXCL9-3 and si-CXCL10-2 fragments were chosen for further experiments (Fig. S6). CM-8 W Mono-S. aureus with knockdown of CXCL9, CXCL10, or both of them was collected after 12 h of infection before treatment with neutrophils or macrophages. We found that CM-8 W Mono-S. aureus with knockdown of either CXCL9 or CXCL10 significantly increased the numbers of both extracellular and intracellular bacterial colonies of S. aureus-infected neutrophils (Fig. 5f-h). However, knockdown of both CXCL9 and CXCL10 didn’t further increase the bacterial load in neutrophils compared with knockdown of either CXCL9 or CXCL10 alone (Fig. 5f-h). In addition, the number of bacterial colonies in BMDMs was also considerably increased by the treatment of CM-8 W Mono-S. aureus with knockdown of CXCL9 or CXCL10 (Fig. 5i and j). Interestingly, knockdown of both CXCL9 and CXCL10 further increased the bacterial load in BMDMs compared with knockdown of either CXCL9 alone (Fig. 5i and j). The above data indicate that CXCL9/10 production from monocytes activated by S. aureus infection may enhance the bactericidal function of neutrophils and macrophages.

CXCR3 signaling in neutrophils and macrophages promotes their bactericidal function

To confirm the role of monocytes-originated CXCL9/10 in the activities of neutrophils and macrophages, we then determined whether blocking CXCR3 signaling could lead to an alteration in their bactericidal function. Blocking CXCR3 with AMG487 increased both the extracellular and intracellular bacterial burdens of neutrophils (Fig. 6a-c). A similar phenotype with an increased S. aureus burden was observed in AMG487-treated BMDMs (Fig. 6d and e). A recent study indicated a bactericide/bacteriostatic function of Teleost CXCL10 against fish pathogens [35]. Thus, to exclude the possible direct effect of CXCL9/10 on suppressing S. aureus, we explored whether inhibition of CXCR3 might block the effect of CXCL9/10 on the bactericidal function of neutrophils and macrophages. As expected, AMG487 treatment significantly ablated the positive effect of CXCL9 or CXCL10 on extracellular and intracellular bacterial killing of neutrophils (Fig. 6f-k). In addition, either CXCL9- or CXCL10-driven antimicrobial activity of macrophages against S. aureus was also blocked by AMG487 (Fig. 6l-n). The above data demonstrated that S. aureus-challenged monocytes from young mice may enhance bactericidal activity of neutrophils and macrophages through the CXCL9/10-CXCR3 axis.

Reduced production of CXCL9/10 in monocytes upon S. aureus challenge contributes to compromised antimicrobial function in middle-aged mice

To test the protective role of CXCL9/10 in an early stage of S. aureus osteomyelitis in mice, we administrated recombinant CXCL9 or CXCL10 to 10-month-old mice with S. aureus osteomyelitis. We found that either CXCL9- or CXCL10-treated mice had a strikingly smaller bacterial burden in bone marrow compared with vehicle-treated ones, as revealed by immunofluorescence staining of S. aureus in infected femurs (Fig. 7a, b, e and f). Additionally, vehicle-treated mice showed extensive cell necrosis and bone marrow lesions around the S. aureus-infected site, while either CXCL9 or CXCL10 treatment significantly improved cellular morphology and tissue structure in S. aureus-infected bone marrow (Fig. 7c, d, g and h).

To determine whether enhanced production of CXCL9/10 in monocytes from young mice might account for increased bactericidal function in neutrophils and macrophages, we applied AMG487 to 8-week-old mice with S. aureus osteomyelitis. Immunofluorescence staining for S. aureus showed significant expansion of bacteria in the bone marrow in AMG487-treated mice compared with vehicle-treated ones (Fig. 7i and j). In line with the increased bacterial loading in bone marrow, cells necrosis and bone marrow lesions were considerably increased after AMG487 treatment in 8-week-old mice (Fig. 7k and l).

Discussion

There are major gaps in understanding the cellular and molecular mechanisms underlying the age-associated decline in the resistance to S. aureus infection in skeleton. Here, using a mice model of S. aureus osteomyelitis, we have identified bone marrow monocytes as a predominant cellular source of CXCL9/10 upon S. aureus challenge. Moreover, we provide a unique insight into the CXCL9 and CXCL10, known to have a strong effect on recruiting other immune cells by acting on the CXCR3 receptor. We have found that they may promote bactericidal function of macrophages and neutrophils in bone marrow. Finally, we have provided evidence that declined production of CXCL9/10 in monocytes upon S. aureus challenge may be responsible for the reduced antibacterial activity of innate immune cells in middle-aged mice. All the data gained by this study may facilitate development of feasible therapeutic approaches for S. aureus osteomyelitis in aged hosts.

An interesting finding of this study is that we have identified a novel function of monocytes as a critical regulator of the innate immunity against S. aureus which may decline with aging. One of known and primary functions of monocytes is differentiation into macrophages and dendritic cells to control infection [36,37,38]. Our work has extended this observation to show that monocytes are critical in control of the antimicrobial defense function of macrophages and neutrophils upon S. aureus infection. Mounting evidence indicates a diminished response in monocytes from whole blood of middle-aged or aged individuals challenged with pattern recognition receptor agonists, resulting in a substantially reduced NF-κB signaling and decreased production of proinflammatory cytokines such as IFN-α, IFN-γ, IL-1β [39, 40]. Our findings also suggest a diminished response in bone marrow monocytes of middle-aged mice following S. aureus infection, leading to impaired bactericidal function of macrophages and neutrophils and increased bacterial burden. These findings suggest that the decreased responsiveness and altered phenotype of monocytes may contribute to age-related immune system impairment, ultimately rendering elderly individuals more susceptible to and experiencing more severe infections [41,42,43]. Consequently, targeting monocytes with specific therapies could be a promising approach for combating S. aureus osteomyelitis in elderly population.

The most important finding of the present study is that CXCL9/10 may play a critical role in controlling the bacterial killing activities of macrophages and neutrophils during S. aureus infection. CXCL9/10, known to be interferon (IFN)-induced angiostatic CXC chemokines, can be expressed by a variety of cells, such as T cells, monocytes, neutrophils, endothelial cells and stromal cells [32, 34, 44]. Our previous work identified an up-regulated expression of CXCL9/10 in young mice femurs with S. aureus osteomyelitis [21]. In the present work, we further revealed that CXCL9/10 production was predominantly induced in monocytes upon S. aureus infection, and its levels in both basal and S. aureus-challenged conditions were declined in middle-aged mice. Although accumulating evidence have supported the redundant functions of CXCL9 and CXCL10 in controlling recruitment, differentiation and proliferation of immune cells in various disease, such as tumor development and viral infections [34, 44, 45], their activities in S. aureus infection remain unclear. Our findings here advanced current understanding of CXCL9/10 function in host defense by connecting monocytes activities with bactericidal functions of macrophages and neutrophils. Furthermore, our findings indicate highly activated CXCL10 in neutrophils challenged with S. aureus challenge in vitro, consistent with previous studies observing elevated CXCL10 and CXCR3 in neutrophils during infection with Salmonella, Aspergillus, or respiratory virus [46,47,48]. Thus, the less responsiveness of neutrophils to combination treatment with CXCL9 and CXCL10 proteins or their knockdown in monocytes may be attributed to heightened activation of CXCL10 expression in neutrophils during S. aureus challenge, or due to differential interaction between CXCL9 and CXCL10 in immune cells [44]. Additional investigations are needed to delineate the cellular sources of CXCL9/10 and their altered response to S. aureus infection during aging in vivo.

The translocation of phosphorylated MLKL to the cell membrane is a hallmark of necroptosis [49], a process that plays an important role in mounting antimicrobial response. Activation of MLKL signaling in neutrophils may promote the production of ROS and the extrusion of bacteriostatic NETs [50]. In models of skin infection or sepsis, MLKL knock-out mice exhibited high bacterial loads [51], underscoring the importance of MLKL in host defense. Thus, the increased levels of phosphorylated MLKL observed in both 8-week-old and 10-month-old mice indicate a host defense mechanism against S. aureus infection. However, the activation of MLKL in macrophages could also lead to membrane permeabilization and the release of pro-inflammatory cytokines such as IL-1β and CXCL10 [52, 53], which have been associated with inflammation-induced tissue damage [53, 54]. Interestingly, our study revealed increased levels of phosphorylated MLKL but a decrease in CXCL10 production in 10-month-old mice following S. aureus infection, potentially due to impaired migration of immune cells like monocytes and neutrophils observed in the present study.

Our previous research, along with other studies, has extensively documented the progressive histopathological changes occurring in S. aureus-infected bone among young mice aged between 8 and 10 weeks. By day 14 post-infection, evidence of periosteal bone formation and bone marrow abscess formation becomes apparent, followed by the emergence of large abscesses, sequestra, intense marrow fibrosis, and femur deformities by day 28 [21, 55, 56]. While our investigations did not extend to evaluating long-term pathological changes in S. aureus-infected bone in aging mice, the observation of cell necrosis in the bone marrow of middle-aged mice, even during the acute stage of infection, suggests a potentially more severe bone destruction process in aged mice. This has significant clinical implications, as older patients with osteomyelitis often experience poor outcomes, including heightened rates of fragility fractures and increased long-term mortality risk [6, 7]. Further research is needed to unravel the mechanisms underlying cellular necrosis during the acute stage of S. aureus osteomyelitis in aged bone marrow.

In conclusion, this study has uncovered that monocyte-derived CXCL9/10 augments the antibacterial activities of macrophages and neutrophils upon S. aureus challenge, and an age-dependent declined production of CXCL9/10 in monocytes upon S. aureus infection contributes to reduced antimicrobial defense in skeleton. This work reveals a novel function of CXCL9/10-CXCR3 axis as a vital component of innate immunity against S. aureus invasion, suggesting that promoted production of CXCL9/10 in monocytes might be an effective strategy in the combat against S. aureus infection in aged skeleton.

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

S. aureus:: Staphylococcus aureus
CXCL9:: C-X-C motif chemokine ligand 9
CXCL10:: C-X-C motif chemokine ligand 10
CXCR3:: C-X-C motif chemokine receptor 3
TSB:: Tryptic soy broth
OD:: Optical density
CFU:: Colony forming unit
PBS:: Phosphate buffer saline
EDTA:: Ethylenediaminetetraacetic acid
H&E:: Hematoxylin and eosin
MLKL:: Mixed-lineage kinase domain-like
DAB:: 3,3-N-Diaminobenzidine tertrahydrochloride
DEGs:: Differential expressed genes
GO:: Gene Ontology
BMDMs:: Bone marrow derived macrophages
ROS:: Reactive oxygen species
NETs:: Neutrophil extracellular traps
DHE:: Dihydroethidium
CM:: Conditional medium
MOI:: Multiplicity of infection
qPCR:: Quantitative real-time PCR

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Acknowledgements

We thank Prof. Liang ** for English proofreading of the manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (82072459, 82272258), Startup Fund for scientific research, Fujian Medical University (2023QH1320).

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Yihuang Lin and Mankai Yang contributed equally to this work..

Authors and Affiliations

Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province, 510515, China
Yihuang Lin, Mankai Yang, Chubin Cheng, Jichang Wu, Bin Yu & **anrong Zhang
Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China
Yihuang Lin, Mankai Yang, Chubin Cheng, Jichang Wu, Bin Yu & **anrong Zhang
Department of Orthopaedics, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, 363000, China
Yihuang Lin

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Yihuang Lin
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Mankai Yang
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Chubin Cheng
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Jichang Wu
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Bin Yu
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**anrong Zhang
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Contributions

Conceptualization, XZ and YL. Mouse experiments, YL, MY, CC and JW. In vitro experiments, YL and MY. Formal analysis, XZ, YL and MY. Original draft, XZ and YL. Supervise, XZ and BY. Critical revision of manuscript: XZ.

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Correspondence to **anrong Zhang.

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All animal experimental protocols were approved by the Animal Care and Use Committee of Nanfang Hospital, Southern Medical University.

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Lin, Y., Yang, M., Cheng, C. et al. Age-related dysregulation of CXCL9/10 in monocytes is linked to impaired innate immune responses in a mouse model of Staphylococcus aureus osteomyelitis. Cell. Mol. Life Sci. 81, 300 (2024). https://doi.org/10.1007/s00018-024-05311-2

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Received: 27 December 2023
Revised: 12 May 2024
Accepted: 10 June 2024
Published: 13 July 2024
DOI: https://doi.org/10.1007/s00018-024-05311-2

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Age-related dysregulation of CXCL9/10 in monocytes is linked to impaired innate immune responses in a mouse model of Staphylococcus aureus osteomyelitis

Abstract

Background

Results

Conclusions

Background

Monocyte-derived CXCL9/10 is critical for the bactericidal function of neutrophils and macrophages from bone marrow

CXCR3 signaling in neutrophils and macrophages promotes their bactericidal function

Reduced production of CXCL9/10 in monocytes upon S. aureus challenge contributes to compromised antimicrobial function in middle-aged mice

Discussion

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Supplementary Material 1

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