PMID- 36726024
OWN - NLM
STAT- MEDLINE
DCOM- 20230203
LR  - 20230316
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 13
IP  - 1
DP  - 2023 Feb 1
TI  - IL-6/ERK signaling pathway participates in type I IFN-programmed, unconventional 
      M2-like macrophage polarization.
PG  - 1827
LID - 10.1038/s41598-022-23721-9 [doi]
LID - 1827
AB  - Type I interferons (IFN-Is) have been harnessed for cancer therapies due to their 
      immunostimulatory functions. However, certain tumor-tolerating activities by 
      IFN-Is also exist, and may potentially thwart their therapeutic effects. In this 
      respect, our previous studies have demonstrated a monocyte-orchestrated, 
      IFN-I-to-IL-4 cytokine axis, which can subsequently drive M2-skewed pro-tumoral 
      polarization of macrophages. Whether other IFN-dependent signals may also 
      contribute to such an unconventional circumstance of M2-like macrophage skewing 
      remain unexplored. Herein, we first unveil IL-6 as another ligand that 
      participates in IFN-dependent induction of a typical M2 marker (ARG1) in 
      transitional monocytes. Indeed, IL-6 significantly promotes IL-4-dependent 
      induction of a major group of prominent M2 markers in mouse bone marrow-derived 
      macrophages (BMDMs) and human peripheral blood-derived macrophages, while it 
      alone does not engage marked increases of these markers. Such a pattern of 
      regulation is confirmed globally by RNAseq analyses in BMDMs, which in turn 
      suggests an association of IL-6-amplified subset of M2 genes with the ERK1/2 
      signaling pathway. Interestingly, pharmacological experiments establish the role 
      of SHP2-ERK cascade in mediating IL-6's enhancement effect on these M2 targets. 
      Similar approaches also validate the involvement of IL-6/ERK signaling in 
      promoting the IFN-dependent, unconventional M2-skewing phenotype in transitional 
      monocytes. Furthermore, an inhibitor of ERK signaling cooperates with an IFN-I 
      inducer to enable a greater antitumor effect, which correlates with suppression 
      of treatment-elicited ARG1. The present work establishes a role of IL-6/ERK 
      signaling in promoting M2-like macrophage polarization, and suggests this axis as 
      a potential therapeutic target for combination with IFN-I-based cancer 
      treatments.
CI  - (c) 2023. The Author(s).
FAU - Yang, Limin
AU  - Yang L
AD  - State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of 
      Model Animals for Disease Study, Model Animal Research Center at Medical School 
      of Nanjing University, Nanjing, 210061, China.
AD  - Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical 
      School, Yancheng, 224006, China.
FAU - Guo, Panpan
AU  - Guo P
AD  - Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of 
      Nanjing University Medical School, Nanjing, 210008, China.
FAU - Wang, Pei
AU  - Wang P
AD  - State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of 
      Model Animals for Disease Study, Model Animal Research Center at Medical School 
      of Nanjing University, Nanjing, 210061, China.
FAU - Wang, Wei
AU  - Wang W
AD  - Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical 
      School, Yancheng, 224006, China. rulerwong@163.com.
AD  - The First People's Hospital of Yancheng, Yancheng, 224006, China. 
      rulerwong@163.com.
FAU - Liu, Jianghuai
AU  - Liu J
AD  - State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of 
      Model Animals for Disease Study, Model Animal Research Center at Medical School 
      of Nanjing University, Nanjing, 210061, China. liujianghuai@nju.edu.cn.
AD  - Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical 
      School, Yancheng, 224006, China. liujianghuai@nju.edu.cn.
AD  - Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing 
      University, Nanjing, 210093, China. liujianghuai@nju.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230201
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Interleukin-6)
RN  - 207137-56-2 (Interleukin-4)
RN  - 0 (Interferon Type I)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Humans
MH  - Interleukin-6/metabolism
MH  - Interleukin-4/metabolism
MH  - Macrophages/metabolism
MH  - Signal Transduction
MH  - *Neoplasms/metabolism
MH  - *Interferon Type I/metabolism
PMC - PMC9892596
COIS- The authors declare no competing interests.
EDAT- 2023/02/03 06:00
MHDA- 2023/02/04 06:00
PMCR- 2023/02/01
CRDT- 2023/02/02 00:02
PHST- 2022/08/14 00:00 [received]
PHST- 2022/11/03 00:00 [accepted]
PHST- 2023/02/02 00:02 [entrez]
PHST- 2023/02/03 06:00 [pubmed]
PHST- 2023/02/04 06:00 [medline]
PHST- 2023/02/01 00:00 [pmc-release]
AID - 10.1038/s41598-022-23721-9 [pii]
AID - 23721 [pii]
AID - 10.1038/s41598-022-23721-9 [doi]
PST - epublish
SO  - Sci Rep. 2023 Feb 1;13(1):1827. doi: 10.1038/s41598-022-23721-9.