Journal
IMMUNOLOGY
Volume 162, Issue 4, Pages 418-433Publisher
WILEY
DOI: 10.1111/imm.13294
Keywords
interleukin-6; lupus; mesangial cell; mitogen-activated protein kinase; neuraminidase; Toll-like receptor 4
Categories
Funding
- Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-16-1-0640]
- NIH Clinical Center Grant [U01 CA242096]
- NIH Exploratory Center Grant [P20 GM103542]
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The study demonstrates how NEU activity and NEU1 specifically mediate the release of IL-6 and other cytokines from lupus-prone MCs, shedding light on the mechanisms involved in kidney inflammation in lupus. These findings suggest a potential therapeutic target for mitigating tissue damage in lupus nephritis.
Previously, we demonstrated neuraminidase (NEU) activity or NEU1 expression, specifically, is increased in the kidneys of lupus mice and urine of human patients with nephritis. Additionally, NEU activity mediates IL-6 secretion from lupus-prone MRL/lpr primary mouse mesangial cells (MCs) in response to an IgG mimic. IL-6 mediates glomerular inflammation and promotes tissue damage in patients and mouse strains with lupus nephritis. This study further elucidates the mechanisms by which NEU activity and NEU1 specifically mediates the release of IL-6 and other cytokines from lupus-prone MCs. We demonstrate significantly increased release of multiple cytokines and NEU activity in MRL/lpr MCs in response to serum from MRL/lpr mice (lupus serum). Inhibiting NEU activity significantly reduced secretion of three of those cytokines: IL-6, GM-CSF and MIP1 alpha. Message levels of Il-6 and Gm-csf were also increased in response to lupus serum and reduced when NEU activity was inhibited. Neutralizing antibodies to cell-surface receptors and MAPK inhibitors in lupus serum- or LPS-stimulated MCs indicate TLR4 and p38 or ERK MAP kinase signalling play key roles in the NEU-mediated secretion of IL-6. Significantly reduced IL-6 release was observed in C57BL/6 (B6) Neu1+/- primary MCs compared with wild-type (Neu1+/+) B6 MCs in response to lupus serum. Additional results show inhibiting NEU activity significantly increases sialic acid-containing N-glycan levels. Together, our novel observations support a role for NEU activity, and specifically NEU1, in mediating release of IL-6 from lupus-prone MCs in response to lupus serum through a TLR4-p38/ERK MAPK signalling pathway that likely includes desialylation of glycoproteins.
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