MerTK negatively regulates Staphylococcus aureus induced inflammatory response via Toll-like receptor signaling in the mammary gland

Zahoor, Arshad; Yang, Ye; Yang, Chao; Khan, Sher Bahadar; Reix, Christine E. Broster; Anwar, Farhan; Guo, Mengyao; Deng, Ganzhen

doi:10.1016/j.molimm.2020.03.007

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…However, the broader link between Mertk and infection has been made in a variety of murine models and human observational studies, giving further credence to our finding. (29)(30)(31)(32)(33)(34)(35) This supports a focus on MERTK and its partners in a search for therapeutics to reduce risk of fatal infection, in addition to potential roles as biomarkers.…”

Section: Discussionmentioning

confidence: 76%

Plasma proteomic associates of infection mortality in UK Biobank

Drozd,

Hamilton,

Cheng

et al. 2024

Preprint

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Background: Infectious diseases are a major cause of mortality in spite of existing public health, anti-microbial and vaccine interventions. We aimed to define plasma proteomic associates of infection mortality and then apply Mendelian randomisation (MR) to yield biomarkers that may be causally associated. Methods: We used UK Biobank plasma proteomic data to associate 2,923 plasma proteins with infection mortality before 31st December 2019 (240 events in 52,520 participants). Since many plasma proteins also predict non-infection mortality, we focussed on those associated with >1.5-fold risk of infection mortality in an analysis excluding survivors. Protein quantitative trait scores (pQTS) were then used to identify whether genetically predicted protein levels also associated with infection mortality. To conduct Two Sample MR, we performed a genome-wide association study (GWAS) of infection mortality using UK Biobank participants without plasma proteomic data (n=363,953 including 984 infection deaths). Findings: After adjusting for clinical risk factors, 1,142 plasma proteins were associated with risk of infection mortality (false discovery rate <0.05). 259 proteins were associated with >1.5-fold increased risk of infection versus non-infection mortality. Of these, we identified genetically predicted increasing MERTK concentration was associated with increased risk of infection mortality. GWAS for infection mortality revealed no SNPs achieving genome-wide statistical significance (p<5x10-8). However, MR supported a causal association between increasing plasma MERTK protein and infection mortality (odds ratio 1.46 per unit; 95% CI 1.15-1.85; p=0.002). Interpretation: Plasma proteomics demonstrates many proteins are associated with infection mortality. MERTK warrants exploration as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 76%

Plasma proteomic associates of infection mortality in UK Biobank

Drozd,

Hamilton,

Cheng

et al. 2024

Preprint

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“…STAT5A and STAT5B fall within signalling pathways for at least two major galactopoietic hormones, prolactin and growth hormone [ 53 ], and have been shown to be involved in regulating the synthesis of both milk fat [ 54 ] and milk proteins such as S1-casein [ 55 ]. STAT1 shows different regulatory activities, but is important for the response to growth hormone during mammary gland growth and development [ 56 ], as well as for the response to bacteria during mastitis [ 57 ]: this latter function is particularly relevant to Lf as the protein has antibacterial properties. In addition to these three STAT-domain TFs, rs110000337 is predicted to alter a binding site for SOX5, a member of the SRY-related HMG-box family of TFs.…”

Section: Discussionmentioning

confidence: 99%

A common regulatory haplotype doubles lactoferrin concentration in milk

Lopdell,

Trevarton,

Moody

et al. 2024

Genet Sel Evol

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Background Bovine lactoferrin (Lf) is an iron absorbing whey protein with antibacterial, antiviral, and antifungal activity. Lactoferrin is economically valuable and has an extremely variable concentration in milk, partly driven by environmental influences such as milking frequency, involution, or mastitis. A significant genetic influence has also been previously observed to regulate lactoferrin content in milk. Here, we conducted genetic mapping of lactoferrin protein concentration in conjunction with RNA-seq, ChIP-seq, and ATAC-seq data to pinpoint candidate causative variants that regulate lactoferrin concentrations in milk. Results We identified a highly-significant lactoferrin protein quantitative trait locus (pQTL), as well as a cislactotransferrin (LTF) expression QTL (cis-eQTL) mapping to the LTF locus. Using ChIP-seq and ATAC-seq datasets representing lactating mammary tissue samples, we also report a number of regions where the openness of chromatin is under genetic influence. Several of these also show highly significant QTL with genetic signatures similar to those highlighted through pQTL and eQTL analysis. By performing correlation analysis between these QTL, we revealed an ATAC-seq peak in the putative promotor region of LTF, that highlights a set of 115 high-frequency variants that are potentially responsible for these effects. One of the 115 variants (rs110000337), which maps within the ATAC-seq peak, was predicted to alter binding sites of transcription factors known to be involved in lactation-related pathways. Conclusions Here, we report a regulatory haplotype of 115 variants with conspicuously large impacts on milk lactoferrin concentration. These findings could enable the selection of animals for high-producing specialist herds.

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“…Similarly, a study reported that SOCS3 inhibits the induction of Prl and activation of STAT5 [134]. Zahoor et al found that merTK reduces the inflammatory changes induced by S. aureus through STATs/SOCS3 signaling [102]. Furthermore, it has been revealed that impaired SOCS1/3 has a crucial role in the susceptibility of mammary epithelial cells to S. aureus infections.…”

Section: Inhibitors Of the Jak-stat Pathway: Role In Mastitis And Milk Productionmentioning

confidence: 94%

“…During the process of inflammation, STAT5B regulates CD4+ T-cells differentiation [101]. STAT1 raised the expression of SOCS3 and SOCS1 in S. aureus-infected mammary epithelial cells [102]. Furthermore, it was reported that upon treatment with JAK inhibitors, the plasma cells in PCM decreased considerably due to the suppression of IL6/STAT/JAK signaling, resulting in the reversion of pathogenesis [91].…”

Section: Role Of Stats In Bovine Mastitismentioning

confidence: 99%

Role of the JAK-STAT Pathway in Bovine Mastitis and Milk Production

Khan

Xiao

et al. 2020

Animals

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The cytokine-activated Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway is a sequence of communications between proteins in a cell, and it is associated with various processes such as cell division, apoptosis, mammary gland development, lactation, anti-inflammation, and immunity. The pathway is involved in transferring information from receptors on the cell surface to the cell nucleus, resulting in the regulation of genes through transcription. The Janus kinase 2 (JAK2), signal transducer and activator of transcription A and B (STAT5 A & B), STAT1, and cytokine signaling suppressor 3 (SOCS3) are the key members of the JAK-STAT pathway. Interestingly, prolactin (Prl) also uses the JAK-STAT pathway to regulate milk production traits in dairy cattle. The activation of JAK2 and STATs genes has a critical role in milk production and mastitis resistance. The upregulation of SOCS3 in bovine mammary epithelial cells inhibits the activation of JAK2 and STATs genes, which promotes mastitis development and reduces the lactational performance of dairy cattle. In the current review, we highlight the recent development in the knowledge of JAK-STAT, which will enhance our ability to devise therapeutic strategies for bovine mastitis control. Furthermore, the review also explores the role of the JAK-STAT pathway in the regulation of milk production in dairy cattle.

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MerTK negatively regulates Staphylococcus aureus induced inflammatory response via Toll-like receptor signaling in the mammary gland

Cited by 7 publications

References 41 publications

Plasma proteomic associates of infection mortality in UK Biobank

Plasma proteomic associates of infection mortality in UK Biobank

A common regulatory haplotype doubles lactoferrin concentration in milk

Role of the JAK-STAT Pathway in Bovine Mastitis and Milk Production

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