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Neuraminidase activity mediates IL-6 production through TLR4 and p38/ERK MAPK signaling in MRL/lpr mesangial cells

Kamala P. Sundararaj, Jessalyn Rodgers, Peggi Angel, View ORCID ProfileBethany Wolf, View ORCID ProfileTamara K. Nowling
doi: https://doi.org/10.1101/2020.01.15.908160
Kamala P. Sundararaj
1Department of Medicine, Division of Rheumatology; Medical University of South Carolina, Charleston, South Carolina
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Jessalyn Rodgers
1Department of Medicine, Division of Rheumatology; Medical University of South Carolina, Charleston, South Carolina
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Peggi Angel
2Department of Cell and Molecular Pharmacology and Experimental Therapeutics; Medical University of South Carolina, Charleston, South Carolina
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Bethany Wolf
3Department of Public Health Sciences; Medical University of South Carolina, Charleston, South Carolina
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Tamara K. Nowling
1Department of Medicine, Division of Rheumatology; Medical University of South Carolina, Charleston, South Carolina
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  • ORCID record for Tamara K. Nowling
  • For correspondence: nowling@musc.edu
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ABSTRACT

Mesangial cells (MCs), considered the immune cell of the kidney, secrete a number of cytokines including IL-6, which serves as an autocrine factor for MCs stimulating proliferation. IL-6 is associated with disease in patients and mouse strains with lupus nephritis, promoting tissue damage. Previously, we demonstrated the activity or levels of the enzyme neuraminidase (NEU) is increased in the kidneys of lupus mice and urine of human patients with nephritis and that NEU activity plays a role in mediating IL-6 secretion from lupus prone MRL/lpr primary mouse MCs. In this study, we further elucidate the mechanisms by which NEU activity mediates cytokine production by primary lupus prone MCs. MRL/lpr primary MCs were cultured with lupus serum to stimulate cytokine production in the absence or presence of NEU activity inhibitor. Our results show lupus serum increases NEU activity, and secretion of GM-CSF and MIP1α, in addition to IL-6, is significantly reduced when NEU activity is inhibited. mRNA expression of Il-6 and Gm-csf was also increased in response to lupus serum, and reduced when NEU activity was inhibited. Using neutralizing antibodies to specific receptors, inhibitors of MAP kinase signaling pathways, and LPS stimulation we show TLR4 and p38/ERK MAPK play a role in NEU-mediated secretion of IL-6. Together, our results suggest NEU activity plays an important role in the response of lupus prone MCs to factor(s) in lupus serum that stimulates IL-6 expression and secretion through TLR4-p38/ERK MAPK signaling, likely through desialyation of one or more glycoproteins in this pathway.

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Posted January 15, 2020.
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Neuraminidase activity mediates IL-6 production through TLR4 and p38/ERK MAPK signaling in MRL/lpr mesangial cells
Kamala P. Sundararaj, Jessalyn Rodgers, Peggi Angel, Bethany Wolf, Tamara K. Nowling
bioRxiv 2020.01.15.908160; doi: https://doi.org/10.1101/2020.01.15.908160
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Neuraminidase activity mediates IL-6 production through TLR4 and p38/ERK MAPK signaling in MRL/lpr mesangial cells
Kamala P. Sundararaj, Jessalyn Rodgers, Peggi Angel, Bethany Wolf, Tamara K. Nowling
bioRxiv 2020.01.15.908160; doi: https://doi.org/10.1101/2020.01.15.908160

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