PMID- 38103643
OWN - NLM
STAT- MEDLINE
DCOM- 20240209
LR  - 20240209
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 300
IP  - 1
DP  - 2024 Jan
TI  - CTRP6 promotes the macrophage inflammatory response, and its deficiency 
      attenuates LPS-induced inflammation.
PG  - 105566
LID - S0021-9258(23)02594-2 [pii]
LID - 10.1016/j.jbc.2023.105566 [doi]
LID - 105566
AB  - Macrophages play critical roles in inflammation and tissue homeostasis, and their 
      functions are regulated by various autocrine, paracrine, and endocrine factors. 
      We have previously shown that CTRP6, a secreted protein of the C1q family, 
      targets both adipocytes and macrophages to promote obesity-linked inflammation. 
      However, the gene programs and signaling pathways directly regulated by CTRP6 in 
      macrophages remain unknown. Here, we combine transcriptomic and phosphoproteomic 
      analyses to show that CTRP6 activates inflammatory gene programs and signaling 
      pathways in mouse bone marrow-derived macrophages (BMDMs). Treatment of BMDMs 
      with CTRP6 upregulated proinflammatory, and suppressed the antiinflammatory, gene 
      expression. We also showed that CTRP6 activates p44/42-MAPK, p38-MAPK, and NF-kappaB 
      signaling pathways to promote inflammatory cytokine secretion from BMDMs, and 
      that pharmacologic inhibition of these signaling pathways markedly attenuated the 
      effects of CTRP6. Pretreatment of BMDMs with CTRP6 also sensitized and 
      potentiated the BMDMs response to lipopolysaccharide (LPS)-induced inflammatory 
      signaling and cytokine secretion. Consistent with the metabolic phenotype of 
      proinflammatory macrophages, CTRP6 treatment induced a shift toward aerobic 
      glycolysis and lactate production, reduced oxidative metabolism, and elevated 
      mitochondrial reactive oxygen species production in BMDMs. Importantly, in 
      accordance with our in vitro findings, BMDMs from CTRP6-deficient mice were less 
      inflammatory at baseline and showed a marked suppression of LPS-induced 
      inflammatory gene expression and cytokine secretion. Finally, loss of CTRP6 in 
      mice also dampened LPS-induced inflammation and hypothermia. Collectively, our 
      findings suggest that CTRP6 regulates and primes the macrophage response to 
      inflammatory stimuli and thus may have a role in modulating tissue inflammatory 
      tone in different physiological and disease contexts.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Xu, Cheng
AU  - Xu C
AD  - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
FAU - Sarver, Dylan C
AU  - Sarver DC
AD  - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
FAU - Lei, Xia
AU  - Lei X
AD  - Department of Biochemistry and Molecular Biology, Oklahoma State University, 
      Stillwater, Oklahoma, USA.
FAU - Sahagun, Ageline
AU  - Sahagun A
AD  - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
FAU - Zhong, Jun
AU  - Zhong J
AD  - Delta Omics Inc, Baltimore, Maryland, USA.
FAU - Na, Chan Hyun
AU  - Na CH
AD  - Department of Neurology, Institute for Cell Engineering, Johns Hopkins University 
      School of Medicine, Baltimore, Maryland, USA.
FAU - Rudich, Assaf
AU  - Rudich A
AD  - Faculty of Health Sciences, Department of Clinical Biochemistry and Pharmacology, 
      Ben-Gurion University of the Negev, Beer-Sheva, Israel.
FAU - Wong, G William
AU  - Wong GW
AD  - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA. Electronic address: gwwong@jhmi.edu.
LA  - eng
GR  - R01 DK084171/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20231214
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adipokines)
RN  - 0 (CTRP6 protein, mouse)
RN  - 0 (Cytokines)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 0 (Lipopolysaccharides)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - 0 (NF-kappa B)
RN  - 0 (Phosphoproteins)
RN  - 0 (Reactive Oxygen Species)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Adipokines/deficiency/genetics/metabolism
MH  - Bone Marrow Cells/cytology
MH  - Cytokines/metabolism
MH  - *Gene Expression Profiling
MH  - Glycolysis
MH  - Hypothermia/complications
MH  - *Inflammation/complications/genetics/immunology/metabolism
MH  - Lactic Acid/biosynthesis
MH  - *Lipopolysaccharides/immunology
MH  - *Macrophages/cytology/immunology/metabolism
MH  - Mice, Inbred C57BL
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - NF-kappa B/metabolism
MH  - *Phosphoproteins/analysis/metabolism
MH  - *Proteomics
MH  - Signal Transduction
MH  - Reactive Oxygen Species/metabolism
PMC - PMC10789631
OTO - NOTNLM
OT  - CTRP
OT  - LPS
OT  - inflammation
OT  - macrophage
OT  - phosphoproteomics
OT  - signaling
OT  - transcriptomics
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2023/12/17 09:44
MHDA- 2024/02/05 06:43
PMCR- 2023/12/14
CRDT- 2023/12/16 19:26
PHST- 2023/05/20 00:00 [received]
PHST- 2023/11/27 00:00 [revised]
PHST- 2023/12/08 00:00 [accepted]
PHST- 2024/02/05 06:43 [medline]
PHST- 2023/12/17 09:44 [pubmed]
PHST- 2023/12/16 19:26 [entrez]
PHST- 2023/12/14 00:00 [pmc-release]
AID - S0021-9258(23)02594-2 [pii]
AID - 105566 [pii]
AID - 10.1016/j.jbc.2023.105566 [doi]
PST - ppublish
SO  - J Biol Chem. 2024 Jan;300(1):105566. doi: 10.1016/j.jbc.2023.105566. Epub 2023 
      Dec 14.