PMID- 26082435
OWN - NLM
STAT- MEDLINE
DCOM- 20160318
LR  - 20221015
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Print)
IS  - 1945-0877 (Linking)
VI  - 8
IP  - 381
DP  - 2015 Jun 16
TI  - Analysis of single-cell cytokine secretion reveals a role for paracrine signaling 
      in coordinating macrophage responses to TLR4 stimulation.
PG  - ra59
LID - 10.1126/scisignal.aaa2155 [doi]
AB  - Macrophages not only produce multiple cytokines but also respond to multiple 
      cytokines, which likely shapes the ultimate response of the population. To 
      determine the role of paracrine signaling in shaping the profile of inflammatory 
      cytokines secreted by macrophages in response to stimulation of Toll-like 
      receptor 4 (TLR4) with lipopolysaccharide (LPS), we combined multiplexed, 
      microwell-based measurements of cytokine secretion by single cells with analysis 
      of cytokine secretion by cell populations. Loss of paracrine signaling as a 
      result of cell isolation reduced the secretion by macrophage-like U937 cells and 
      human monocyte-derived macrophages (MDMs) of a subset of LPS-stimulated 
      cytokines, including interleukin-6 (IL-6) and IL-10. Graphical Gaussian modeling 
      (GGM) of the single-cell data defined a regulatory network of paracrine signals, 
      which was validated experimentally in the population through antibody-mediated 
      neutralization of individual cytokines. Tumor necrosis factor-alpha (TNF-alpha) was the 
      most influential cytokine in the GGM network. Paracrine signaling by TNF-alpha 
      secreted from a small subpopulation of "high-secreting" cells was necessary, but 
      not sufficient, for the secretion of large amounts of IL-6 and IL-10 by the cell 
      population. Decreased relative IL-10 secretion by isolated MDMs was linked to 
      increased TNF-alpha secretion, suggesting that inhibition of the inflammatory 
      response also depends on paracrine signaling. Our results reveal a previously 
      uncharacterized role for cell-to-cell communication within a population in 
      coordinating a rapid innate immune response despite underlying cell-to-cell 
      heterogeneity.
CI  - Copyright (c) 2015, American Association for the Advancement of Science.
FAU - Xue, Qiong
AU  - Xue Q
AD  - Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
FAU - Lu, Yao
AU  - Lu Y
AD  - Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
FAU - Eisele, Markus R
AU  - Eisele MR
AD  - Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. 
      Institute for System Dynamics, University of Stuttgart, 70569 Stuttgart, Germany.
FAU - Sulistijo, Endah S
AU  - Sulistijo ES
AD  - Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
FAU - Khan, Nafeesa
AU  - Khan N
AD  - Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
FAU - Fan, Rong
AU  - Fan R
AD  - Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. 
      rong.fan@yale.edu kathryn.miller-jensen@yale.edu.
FAU - Miller-Jensen, Kathryn
AU  - Miller-Jensen K
AD  - Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. 
      Department of Molecular, Cellular, and Developmental Biology, Yale University, 
      New Haven, CT 06520, USA. rong.fan@yale.edu kathryn.miller-jensen@yale.edu.
LA  - eng
GR  - U01 CA164252/CA/NCI NIH HHS/United States
GR  - U54 CA143798/CA/NCI NIH HHS/United States
GR  - U54-CA143798/CA/NCI NIH HHS/United States
GR  - U01-CA164252/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150616
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (TLR4 protein, human)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
MH  - Cytokines/*immunology
MH  - Humans
MH  - Lipopolysaccharides/*pharmacology
MH  - Macrophages/cytology/*immunology
MH  - Paracrine Communication/*drug effects/immunology
MH  - Signal Transduction/*drug effects/immunology
MH  - Toll-Like Receptor 4/agonists/*immunology
MH  - U937 Cells
PMC - PMC5735825
MID - NIHMS922911
COIS- Competing interests: R.F. has substantial financial interests (including equity) 
      in Isoplexis.
EDAT- 2015/06/18 06:00
MHDA- 2016/03/19 06:00
PMCR- 2017/12/19
CRDT- 2015/06/18 06:00
PHST- 2015/06/18 06:00 [entrez]
PHST- 2015/06/18 06:00 [pubmed]
PHST- 2016/03/19 06:00 [medline]
PHST- 2017/12/19 00:00 [pmc-release]
AID - 8/381/ra59 [pii]
AID - 10.1126/scisignal.aaa2155 [doi]
PST - epublish
SO  - Sci Signal. 2015 Jun 16;8(381):ra59. doi: 10.1126/scisignal.aaa2155.