TY - JOUR
T1 - Upregulation of proinflammatory bradykinin peptides in systemic lupus erythematosus and rheumatoid arthritis
AU - Vanarsa, Kamala
AU - Henderson, Jared
AU - Soomro, Sanam
AU - Qin, Ling
AU - Zhang, Ting
AU - Jordan, Nicole
AU - Putterman, Chaim
AU - Blanco, Irene
AU - Saxena, Ramesh
AU - Mohan, Chandra
N1 - Publisher Copyright:
Copyright © 2020 by The American Association of Immunologists, Inc.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - Our recent study has implicated bradykinin (BK) signaling as being of pathogenic importance in lupus. This study aims to investigate the biomarker potential of BK peptides, BK and BK-des-arg-9, in lupus and other rheumatic autoimmune diseases. Sera from systemic lupus erythematosus (SLE) patients and healthy subjects were screened for BK and BK-des-arg-9 by liquid chromatography-mass spectrometry metabolomics. Serum from 6-mo-old C57BL/6 mice and three murine lupus strains were also screened for the two peptides by metabolomics. Given the promising initial screening results, validation of these two peptides was next conducted using multiple reaction monitoring in larger patient cohorts. In initial metabolomics screening, BK-des-arg-9 was 22-fold higher in SLE serum and 106-fold higher in mouse lupus serum compared with healthy controls. In validation assays using multiple reaction monitoring and quadrupole time-of-flight mass spectrometry, BK and BK-des-arg-9 showed significant elevations in SLE serum compared with controls (p < 0.0001; area under the curve = 0.79-0.88), with a similar but less pronounced increase being noted in rheumatoid arthritis serum. Interestingly, increased renal SLE disease activity index in lupus patients was associated with reduced circulating BK-des-arg-9, and the reasons for this remain to be explored. To sum, increased conversion of BK to the proinflammatory metabolite BK-des-arg-9 appears to be a common theme in systemic rheumatic diseases. Besides serving as an early marker for systemic autoimmunity, independent studies also show that this metabolic axis may also be a pathogenic driver and therapeutic target in lupus.
AB - Our recent study has implicated bradykinin (BK) signaling as being of pathogenic importance in lupus. This study aims to investigate the biomarker potential of BK peptides, BK and BK-des-arg-9, in lupus and other rheumatic autoimmune diseases. Sera from systemic lupus erythematosus (SLE) patients and healthy subjects were screened for BK and BK-des-arg-9 by liquid chromatography-mass spectrometry metabolomics. Serum from 6-mo-old C57BL/6 mice and three murine lupus strains were also screened for the two peptides by metabolomics. Given the promising initial screening results, validation of these two peptides was next conducted using multiple reaction monitoring in larger patient cohorts. In initial metabolomics screening, BK-des-arg-9 was 22-fold higher in SLE serum and 106-fold higher in mouse lupus serum compared with healthy controls. In validation assays using multiple reaction monitoring and quadrupole time-of-flight mass spectrometry, BK and BK-des-arg-9 showed significant elevations in SLE serum compared with controls (p < 0.0001; area under the curve = 0.79-0.88), with a similar but less pronounced increase being noted in rheumatoid arthritis serum. Interestingly, increased renal SLE disease activity index in lupus patients was associated with reduced circulating BK-des-arg-9, and the reasons for this remain to be explored. To sum, increased conversion of BK to the proinflammatory metabolite BK-des-arg-9 appears to be a common theme in systemic rheumatic diseases. Besides serving as an early marker for systemic autoimmunity, independent studies also show that this metabolic axis may also be a pathogenic driver and therapeutic target in lupus.
UR - http://www.scopus.com/inward/record.url?scp=85088207409&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1801167
DO - 10.4049/jimmunol.1801167
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C2 - 32540998
AN - SCOPUS:85088207409
SN - 0022-1767
VL - 205
SP - 369
EP - 376
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -