Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen

Onyishi, Chinaemerem U.; Desanti, Guillaume E.; Wilkinson, Alex L; Lara-Reyna, Samuel; Frickel, Eva‐Maria; Fejér, György; Olivier, Christophe; Bryant, Clare; Mukhopadhyay, Subhankar; Gordon, Siamon; May, Robin C.

doi:10.1038/s41467-023-40635-w

Cited by 6 publications

(5 citation statements)

References 62 publications

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“…However, the marked increase in macrophage MSR1 gene expression levels and shift towards a more M2-like inflammation resolving (TNF-alpha low CHI3L3/MRC1/FIZZ1 high ) macrophage phenotype noted in our current in vivo setting do concur with the assumption that PRG4 executes its biological actions primarily by blocking TLR4 function (Alquraini et al, 2015). Onyishi et al (2023) have found that genetic TLR4 deficiency in bone marrow-derived macrophages similarly increases MSR1 expression levels. Furthermore, Perera et al (2001) and Mann et al (2004) have shown that genetic lack of TLR4 is also associated with a reduced transcription and secretion of TNF-alpha in response to B. bronchiseptica, lipopolysaccharide or taxol exposure.…”

Section: Discussionsupporting

confidence: 84%

Recombinant human proteoglycan 4 lowers inflammation and atherosclerosis susceptibility in female low‐density lipoprotein receptor knockout mice

Hoekstra,

Snip,

Janusz

et al. 2024

The Journal of Physiology

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Recombinant human proteoglycan 4 (rhPRG4) is a macromolecular mucin‐like glycoprotein that is classically studied as a lubricant within eyes and joints. Given that endogenously produced PRG4 is present within atherosclerotic lesions and genetic PRG4 deficiency increases atherosclerosis susceptibility in mice, in the current study we investigated the anti‐atherogenic potential of chronic rhPRG4 treatment. Female low‐density lipoprotein receptor knockout mice were fed an atherogenic Western‐type diet for 6 weeks and injected three times per week intraperitoneally with 0.5 mg rhPRG4 or PBS as control. Treatment with rhPRG4 was associated with a small decrease in plasma‐free cholesterol levels, without a change in cholesteryl ester levels. A marked increase in the number of peritoneal foam cells was detected in response to the peritoneal rhPRG4 administration, which could be attributed to elevated peritoneal leukocyte MSR1 expression levels. However, rhPRG4‐treated mice exhibited significantly smaller aortic root lesions of 278 ± 21 × 103 μm2 compared with 339 ± 15 × 103 μm2 in the aortic root of control mice. The overall decreased atherosclerosis susceptibility coincided with a shift in the monocyte and macrophage polarization states towards the patrolling and anti‐inflammatory M2‐like phenotypes, respectively. Furthermore, rhPRG4 treatment significantly reduced macrophage gene expression levels as well as plasma protein levels of the pro‐inflammatory/pro‐atherogenic cytokine TNF‐alpha. In conclusion, we have shown that peritoneal administration and subsequent systemic exposure to rhPRG4 beneficially impacts the inflammatory state and reduces atherosclerosis susceptibility in mice. Our findings highlight that PRG4 is not only a lubricant but also acts as an anti‐inflammatory agent. imageKey points Endogenously produced proteoglycan 4 is found in atherosclerotic lesions and its genetic deficiency in mice is associated with enhanced atherosclerosis susceptibility. In this study we investigated the anti‐atherogenic potential of chronic treatment with recombinant human PRG4 in hypercholesterolaemic female low‐density lipoprotein receptor knockout mice. We show that recombinant human PRG4 stimulates macrophage foam cell formation, but also dampens the pro‐inflammatory state of monocyte/macrophages, eventually leading to a significant reduction in plasma TNF‐alpha levels and a lowered atherosclerosis susceptibility. Our findings highlight that peritoneal recombinant human PRG4 treatment can execute effects both locally and systemically and suggest that it will be of interest to study whether rhPRG4 treatment is also able to inhibit the progression and/or induce regression of previously established atherosclerotic lesions.

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Section: Discussionsupporting

confidence: 84%

Recombinant human proteoglycan 4 lowers inflammation and atherosclerosis susceptibility in female low‐density lipoprotein receptor knockout mice

Hoekstra,

Snip,

Janusz

et al. 2024

The Journal of Physiology

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“…Furthermore, MR analysis of CTSB and various macrophage receptors revealed the mutual relationship between CTSB levels and macrophage scavenger receptor types I and II; this indicates that the effect of CTSB on macrophages is related to MSR-A upregulation. As a pattern recognition receptor, MSR plays a vital role in phagocytosis 30 and proin ammatory cytokine release of macrophages 31 .…”

Section: Discussionmentioning

confidence: 99%

Causal relationship between cathepsins and esophageal adenocarcinoma: Mendelian randomization and single-cell RNA sequencing analysis

Tian,

Li,

Tang

et al. 2024

Preprint

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The incidence of esophageal adenocarcinoma (EAC) has significantly increased, particularly in Western countries. Cathepsins are a group of lysosomal proteolytic enzymes; they are associated with the occurrence and progression of various tumors. However, the causal relationship between the cathepsin family and EAC remains unelucidated. To investigate this association, Mendelian randomization (MR) and bioinformatics analyses of single-cell RNA sequencing (scRNA-seq) data were performed. MR analyses revealed that high cathepsin B (CTSB) levels decreased EAC risk. Furthermore, scRNA-seq revealed that CTSB expression was primarily distributed in macrophages. In addition, MR analysis of CTSB and macrophage scavenger receptor types I and II verified their interrelationship; CTSB primarily affects the proinflammatory phenotype of macrophages. Our findings suggest that CTSB levels affect EAC progression by regulating the expression of macrophage scavenger receptor types I and II, which induce the proinflammatory phenotypes of macrophages. Therefore, targeting CTSB may provide avenues for EAC diagnosis and treatment.

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“…An in vitro study by Onyishi et al. investigated the role of TLR4 in phagocytosis, where they found that loss of TLR4 function increased phagocytosis of unopsonised cryptococci by murine and human macrophages ( 72 ).…”

Section: Implant Materials and Inflammationmentioning

confidence: 99%

Modelling of macrophage responses to biomaterials in vitro: state-of-the-art and the need for the improvement

Piatnitskaia,

Rafikova,

Bilyalov

et al. 2024

Front. Immunol.

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The increasing use of medical implants in various areas of medicine, particularly in orthopedic surgery, oncology, cardiology and dentistry, displayed the limitations in long-term integration of available biomaterials. The effective functioning and successful integration of implants requires not only technical excellence of materials but also consideration of the dynamics of biomaterial interaction with the immune system throughout the entire duration of implant use. The acute as well as long-term decisions about the efficiency of implant integration are done by local resident tissue macrophages and monocyte-derived macrophages that start to be recruited during tissue damage, when implant is installed, and are continuously recruited during the healing phase. Our review summarized the knowledge about the currently used macrophages-based in vitro cells system that include murine and human cells lines and primary ex vivo differentiated macrophages. We provided the information about most frequently examined biomarkers for acute inflammation, chronic inflammation, foreign body response and fibrosis, indicating the benefits and limitations of the model systems. Particular attention is given to the scavenging function of macrophages that controls dynamic composition of peri-implant microenvironment and ensures timely clearance of microorganisms, cytokines, metabolites, extracellular matrix components, dying cells as well as implant debris. We outline the perspective for the application of 3D systems for modelling implant interaction with the immune system in human tissue-specific microenvironment avoiding animal experimentation.

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Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen

Cited by 6 publications

References 62 publications

Recombinant human proteoglycan 4 lowers inflammation and atherosclerosis susceptibility in female low‐density lipoprotein receptor knockout mice

Recombinant human proteoglycan 4 lowers inflammation and atherosclerosis susceptibility in female low‐density lipoprotein receptor knockout mice

Causal relationship between cathepsins and esophageal adenocarcinoma: Mendelian randomization and single-cell RNA sequencing analysis

Modelling of macrophage responses to biomaterials in vitro: state-of-the-art and the need for the improvement

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