Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization

Nature Immunology volume 19, pages 561–570 (2018)Cite this article

Subjects

Abstract

Polarization of macrophages into pro-inflammatory or anti-inflammatory states has distinct metabolic requirements, with mechanistic target of rapamycin (mTOR) kinase signaling playing a critical role. However, it remains unclear how mTOR regulates metabolic status to promote polarization of these cells. Here we show that an mTOR–Semaphorin 6D (Sema6D)–Peroxisome proliferator receptor γ (PPARγ) axis plays critical roles in macrophage polarization. Inhibition of mTOR or loss of Sema6D blocked anti-inflammatory macrophage polarization, concomitant with severe impairments in PPARγ expression, uptake of fatty acids, and lipid metabolic reprogramming. Macrophage expression of the receptor Plexin-A4 is responsible for Sema6D-mediated anti-inflammatory polarization. We found that a tyrosine kinase, c-Abl, which associates with the cytoplasmic region of Sema6D, is required for PPARγ expression. Furthermore, Sema6D is important for generation of intestinal resident CX3CR1hi macrophages and prevents development of colitis. Collectively, these findings highlight crucial roles for Sema6D reverse signaling in macrophage polarization, coupling immunity, and metabolism via PPARγ.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: mTOR activity-dependent Sema6D expression is required for anti-inflammatory macrophage polarization.
Fig. 2: Sema6d–/– mice exhibit defective anti-inflammatory macrophage polarization and exaggerated inflammatory responses.
Fig. 3: Sema6D–PPARγ signaling is indispensable for fatty-acid uptake and metabolic reprogramming.
Fig. 4: Sema6D reverse signaling promotes anti-inflammatory macrophage polarization via the tyrosine kinase c-Abl.
Fig. 5: Sema6D signaling is critical for anti-inflammatory properties of CX3CR1hi intestinal macrophages.
Fig. 6: Sema6d–/– myeloid cells predispose mice to colitis.

Similar content being viewed by others

References

  1. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Galli, S. J., Borregaard, N. & Wynn, T. A. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat. Immunol. 12, 1035–1044 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions. Immunity 32, 593–604 (2010).

    Article  PubMed  CAS  Google Scholar 

  4. Bouhlel, M. A. et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 6, 137–143 (2007).

    Article  PubMed  CAS  Google Scholar 

  5. Liao, X. et al. Krüppel-like factor 4 regulates macrophage polarization. J. Clin. Invest. 121, 2736–2749 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Satoh, T. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 11, 936–944 (2010).

    Article  PubMed  CAS  Google Scholar 

  7. Odegaard, J. I. et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Huang, S. C. et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol. 15, 846–855 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Düvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Galván-Peña, S. & O’Neill, L. A. Metabolic reprograming in macrophage polarization. Front. Immunol. 5, 420 (2014).

    PubMed  PubMed Central  Google Scholar 

  11. Howell, J. J. & Manning, B. D. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol. Metab. 22, 94–102 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Weichhart, T., Hengstschläger, M. & Linke, M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 15, 599–614 (2015).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Chen, W. et al. Macrophage-induced tumor angiogenesis is regulated by the TSC2-mTOR pathway. Cancer Res. 72, 1363–1372 (2012).

    Article  PubMed  CAS  Google Scholar 

  14. Kimura, T. et al. Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals. Nat. Commun. 7, 13130 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Rocher, C. & Singla, D. K. SMAD-PI3K-Akt-mTOR pathway mediates BMP-7 polarization of monocytes into M2 macrophages. PLoS One 8, e84009 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Sahin, E. et al. Macrophage PTEN regulates expression and secretion of arginase I modulating innate and adaptive immune responses. J. Immunol. 193, 1717–1727 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kolodkin, A. L., Matthes, D. J. & Goodman, C. S. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75, 1389–1399 (1993).

    Article  PubMed  CAS  Google Scholar 

  18. Pasterkamp, R. J. & Kolodkin, A. L. Semaphorin junction: making tracks toward neural connectivity. Curr. Opin. Neurobiol. 13, 79–89 (2003).

    Article  PubMed  CAS  Google Scholar 

  19. Kang, S. & Kumanogoh, A. Semaphorins in bone development, homeostasis, and disease. Semin. Cell Dev. Biol. 24, 163–171 (2013).

    Article  PubMed  CAS  Google Scholar 

  20. Kang, S. et al. Intestinal epithelial cell-derived semaphorin 7A negatively regulates development of colitis via αvβ1 integrin. J. Immunol. 188, 1108–1116 (2012).

    Article  PubMed  CAS  Google Scholar 

  21. Kumanogoh, A. & Kikutani, H. Immunological functions of the neuropilins and plexins as receptors for semaphorins. Nat. Rev. Immunol. 13, 802–814 (2013).

    Article  PubMed  CAS  Google Scholar 

  22. Suzuki, K. et al. Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature 446, 680–684 (2007).

    Article  PubMed  CAS  Google Scholar 

  23. O'Connor, B. P. et al. Semaphorin 6D regulates the late phase of CD4+. T cell primary immune responses. Proc. Natl Acad. Sci. USA 105, 13015–13020 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Toyofuku, T. et al. Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev. 18, 435–447 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Watarai, H. et al. PDC-TREM, a plasmacytoid dendritic cell-specific receptor, is responsible for augmented production of type I interferon. Proc. Natl Acad. Sci,. USA 105, 2993–2998 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Toyofuku, T. et al. Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat. Cell Biol. 6, 1204–1211 (2004).

    Article  PubMed  CAS  Google Scholar 

  27. Byles, V. et al. The TSC-mTOR pathway regulates macrophage polarization. Nat. Commun. 4, 2834 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Zhu, L. et al. TSC1 controls macrophage polarization to prevent inflammatory disease. Nat. Commun. 5, 4696 (2014).

    Article  PubMed  CAS  Google Scholar 

  29. Martinez, F. O., Sica, A., Mantovani, A. & Locati, M. Macrophage activation and polarization. Front. Biosci. 13, 453–461 (2008).

    Article  PubMed  CAS  Google Scholar 

  30. Parsa, R. et al. Adoptive transfer of immunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice. Diabetes 61, 2881–2892 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Kreider, T., Anthony, R. M., Urban, J. F. Jr. & Gause, W. C. Alternatively activated macrophages in helminth infections. Curr. Opin. Immunol. 19, 448–453 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Reese, T. A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Lawrence, T. & Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat. Rev. Immunol. 11, 750–761 (2011).

    Article  PubMed  CAS  Google Scholar 

  34. Angela, M. et al. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells. Nat. Commun. 7, 13683 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Laplante, M. & Sabatini, D. M. An emerging role of mTOR in lipid biosynthesis. Curr. Biol. 19, R1046–R1052 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Takegahara, N. et al. Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat. Cell Biol. 8, 615–622 (2006).

    Article  PubMed  CAS  Google Scholar 

  37. Wen, H., Lei, Y., Eun, S. Y. & Ting, J. P. Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm. J. Exp. Med. 207, 2943–2957 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Zigmond, E. et al. Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37, 1076–1090 (2012).

    Article  PubMed  CAS  Google Scholar 

  39. Hu, X. et al. Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression. Sci. Rep. 6, 26252 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Tybulewicz, V. L., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163 (1991).

    Article  PubMed  CAS  Google Scholar 

  41. Liberatore, R. A., Goff, S. P. & Nunes, I. NF-kappaB activity is constitutively elevated in c-Abl null fibroblasts. Proc. Natl Acad. Sci. USA 106, 17823–17828 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Keshet, R. et al. c-Abl tyrosine kinase promotes adipocyte differentiation by targeting PPAR-gamma 2. Proc. Natl Acad. Sci. USA 111, 16365–16370 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Inoue for technical support. This work was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to S. Kang); grants from AMED-CREST (JP17gm0410015) and AMED (to A.K.); COI stream and SRIP grants from MEXT (to A.K.); and grants from the Ministry of Health, Labour and Welfare of Japan (to A.K.).

Author information

Author notes

  1. These authors contributed equally: Sujin Kang, Yoshimitsu Nakanishi.

Authors and Affiliations

  1. Department of Immunopathology, Immunology Frontier Research Center, Osaka University, Suita City, Osaka, Japan

    Sujin Kang, Yoshimitsu Nakanishi, Yoshiyuki Kioi, Tetsuya Kimura, Hyota Takamatsu, Shohei Koyama, Satoshi Nojima, Masayuki Nishide, Yoshitomo Hayama, Yuhei Kinehara, Yasuhiro Kato, Takeshi Nakatani, Toshihiko Toyofuku & Atsushi Kumanogoh

  2. Department of Respiratory Medicine and Clinical Immunology, Graduate School of medicine, Osaka University, Suita City, Osaka, Japan

    Sujin Kang, Yoshimitsu Nakanishi, Yoshiyuki Kioi, Hyota Takamatsu, Shohei Koyama, Masayuki Nishide, Yoshitomo Hayama, Yuhei Kinehara, Yasuhiro Kato, Takeshi Nakatani & Atsushi Kumanogoh

  3. Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita City, Osaka, Japan

    Daisuke Okuzaki

  4. Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Suita City, Osaka, Japan

    Junichi Takagi

  5. Department of Immune Regulation, Immunology Frontier Research Center, Osaka University, Suita City, Osaka, Japan

    Sujin Kang

  6. Department of Immunology and Regenerative Medicine, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan

    Toshihiko Toyofuku

  7. Department of Pathology, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan

    Satoshi Nojima

  8. RIKEN Brain Science Institute, Laboratory for Molecular Mechanisms of Thalamus Development, Saitama, Japan

    Tomomi Shimogori

Authors
  1. Sujin Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshimitsu Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshiyuki Kioi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daisuke Okuzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tetsuya Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hyota Takamatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shohei Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Satoshi Nojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masayuki Nishide
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshitomo Hayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuhei Kinehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yasuhiro Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Takeshi Nakatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Tomomi Shimogori
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Junichi Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Toshihiko Toyofuku
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Atsushi Kumanogoh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S. Kang designed and performed most of the experimental work. S. Kang and A.K. wrote the manuscript. A.K. provided important suggestions. Y.N and Y. Kioi performed the experiments and analyzed data. T.K., H.T., S. Koyama, S.N., M.N., Y.H., Y. Kato, Y. Kinehara, T.S., and T.N. performed some experiments. J.T. designed Sema6D mutant constructs. T.T the full-length of Sema6D expression vector and assisted with Seahorse analysis. D.O. performed gene-expression microarrays and deposited the data. All authors participated in discussion of the manuscript.

Corresponding authors

Correspondence to Sujin Kang or Atsushi Kumanogoh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Integrated supplementary information

Supplementary Figure 1 Sema6D deficiency does not affect macrophage differentiation or immune cell development.

(a) Representative flow cytometry data for Sema6D expression in IL-4 stimulated WT BMDMs after Torin1 treatment. (b) Expression of Sema6d mRNA in IL-4–stimulated WT BMDMs after rapamycin treatment, evaluated by quantitative real-time PCR. Expression levels of target genes were normalized to the corresponding level of Gapdh mRNA. (c) Expression of Sema6d mRNA in various immune subpopulations, including bone marrow dendritic cells (BMDCs), peritoneal macrophages (PEC M), GM-CSF–derived macrophages (GM-CSF M), M-CSF–derived macrophages (M-CSF M), activated T cells stimulated with anti-CD3 and anti-CD28 (mature T), and B220 + cells. Expression levels of target genes were normalized to the corresponding level of Gapdh mRNA. (d, e) Representative flow cytometry data for immune populations in spleen (d) and bone marrow (e). Eight-week-old mice were used. (f) Representative flow cytometry data for CD11b, F4/80, and TLR4 expression in M-CSF–derived BMDMs at steady state. *P < 0.05, **P < 0.01, ***P < 0.005. P-values were determined using one-way ANOVA (b). Data are representative of independent experimental replicates, and are presented as means ± SD (n = 3 (b) samples per group).

Supplementary Figure 2 Sema6d−/− BMDMs are refractory to alternative activated macrophage polarization.

(a) Pparg, Retnla, Arg1, and Chi3l1 mRNA expression in WT and Sema6d−/− BMDMs after stimulation with 100 ng/ml IL-4 for the indicated times, as determined by quantitative real-time PCR. (b) Mrc1, Retnla, and Bcl3 mRNA expression in WT and Sema6d−/− BMDMs stimulated with 10 ng/ml IL-10 for 48 hrs. (c) Arg1, Retnla, and Chi3l1 mRNA expression in WT and Sema6d−/− BMDMs stimulated with 100 ng/ml IL-13 for 48 hrs. (d) Arg1, Relm, and Il10 mRNA expression in freshly isolated PECs from WT and Sema6d−/− mice after stimulation with IL-4 for 48 hrs, as determined by quantitative real-time PCR. (e) IL-6, IL-10, and IL-12p40 production in freshly isolated PECs from WT and Sema6d−/− mice after stimulation with LPS + IFN-γ for 4 hrs, as detected by ELISA. Expression of IL-4 receptor (Cd124) (f) and Jak1 and Jak3 (g) was detected by quantitative real-time PCR in IL-4–induced WT and Sema6d−/− BMDMs. (h) Immunoblot analysis of the levels of phospho-STAT6 in WT and Sema6d−/− BMDMs after IL-4 treatment. *P < 0.05, **P < 0.01, ***P < 0.005. P-values were determined using unpaired, two-tailed Student's t-tests (b–e). Data are representative of three independent experimental replicates, and are presented as means ± SD [n = 1 (a), n = 3 (b–g) samples per group].

Supplementary Figure 3 PPARγ signaling is a downstream pathway of Sema6D reverse signaling in macrophages.

(a) Canonical pathway analysis using differentially expressed genes (DEGs) based on RNA-seq data from WT and Sema6d−/− BMDMs under LPS + IFN-γ stimulation. Dot size relates to the number of differentially expressed genes. (b) Upstream regulator analysis of genes downregulated in Sema6d−/− BMDMs under IL-4 stimulation. All data sets were examined by Ingenuity Pathway Analysis (Qiagen Bioinformatics).

Supplementary Figure 4 STAT1 and mTOR activities are normal, but PPARγ expression is impaired, in inflammatory Sema6d−/− macrophages.

(a, b) Activity of phospho-STAT1 in WT and Sema6d−/− BMDMs after LPS (a) or IFN-γ (b) stimulation was detected by western blotting. (c) Phospho-AKT and phopho-S6K in WT and Sema6d−/− BMDMs after LPS stimulation for the indicated times were detected by western blotting. (d) Pparg mRNA expression in WT and Sema6d−/− BMDMs was measured by quantitative real-time PCR after stimulation with LPS, IFN-γ, or LPS + IFN-γ for 4 hrs. (e) Quantitative real-time PCR analyses were performed to measure Nos2 and Il6 mRNA expression in Sema6d−/− BMDMs expressing empty vector, Sema6D (full length), or PPARγ (full length) after LPS + IFN-γ stimulation for 6 hrs. *P < 0.05, **P < 0.01, ***P < 0.005. P-values were determined using unpaired, two-tailed Student's t-test (d) and one-way ANOVA (e). Data are representative of two (e) or three (a–d) independent experimental replicates, and are presented as means ± SD (n = 3 (d, e) samples per group).

Supplementary Figure 5 Sema6D and PPARγ act sequentially, but not in parallel, to regulate anti-inflammatory macrophage polarization.

(a) Immunoblot analysis of PPARγ in Sema6d−/− BMDMs expressing empty vector or Sema6D (full length) after IL-4 stimulation for 48 hrs. (b) Immunoblot analysis of PPARγ expression in WT and Sema6d−/− BMDMs expressing empty vector or PPARγ (full length) after IL-4 stimulation for 24 hrs. (c) Chi3l1 and Arg1 mRNA expression in WT and Sema6d−/− BMDMs expressing empty vector (−) or PPARγ-full length (+) after stimulation with IL-4 for 24 hrs, as determined by quantitative real-time PCR. (d) Experimental protocol for Supplementary Figure 5e. (e) Chi3l1 and Pparg mRNA expression in WT and Sema6d−/− BMDMs expressing empty (−) or Sema6D-full length (+), pre-treated with GW9662 for 3 days following stimulation with IL-4 for 24 hrs, as determined by quantitative real-time PCR. (f) Quantitative real-time PCR analysis of relative expression of Acsl3 and Fads2 in WT and Sema6d−/− IL-4 stimulated BMDMs. (g) Extracellular acidification rate (ECAR) of indicated cells at baseline and after glucose, oligomycin, and 2-deoxyglucose treatment. *P < 0.05, **P < 0.01, ***P < 0.005. P-values were determined using one-way ANOVA (c, e). Data are representative of two (a–e, g) or three (f) independent experimental replicates, and are presented as means ± SD [n = 3 (c, e, f) samples per group].

Supplementary Figure 6 Sema6D reverse signaling controls macrophage polarization.

(a) Retnla, Chi3l1, and Pparg mRNA expression in WT, Sema6d−/−, and Plxna1−/− BMDMs after IL-4 stimulation for 48 hrs, as determined by quantitative real-time PCR. (b) IL-6, IL-10, and IL-12p40 production in WT, Sema6d−/−, and Plxna1−/− BMDMs after stimulation with LPS plus IFN-γ for 4 hrs, as determined by ELISA. (c) Immunoblot analysis of PPARγ in Sema6d−/− BMDMs expressing empty vector, ∆IC, or Sema6D after IL-4 stimulation. (d) Representative flow cytometry data of Sema6D expression in wild-type- BMDM, LPS stimulated BMDM, and IL-4 stimulated BMDMs. (e) Flow cytometry analysis of neuropilin-1 (NP-1) expression in BMDM and LPS BMDMs. (f) Immunoblot analysis of phosphorylation of c-Abl in WT and Sema6d−/− BMDMs after IL-4 stimulation, followed by starvation. Lysates of IL-4 stimulated WT or Sema6d−/− BMDMs were immunoprecipitated with anti-c-Abl antibodies. Immunoprecipitates were immunoblotted with the indicated antibodies. (g) Schematic model of the mechanism of Sema6D reverse signaling leading to lipid metabolism during macrophage polarization. During IL-4–induced anti-inflammatory activation, mTOR is activated and upregulates Sema6D, which in turn activates c-Abl kinase to promote PPARγ expression. Activated PPARγ mediates fatty acid uptake and metabolic reprogramming, which are essential events for full anti-inflammatory activation. This Sema6D–PPARγ axis signaling confers anti-inflammatory properties on CX3CR1hi intestinal macrophage and prevents development of colitis.

Supplementary Figure 7

Uncropped blots.

Supplementary information

Supplementary Figures and Tables

Supplementary Figures 1–7 and Supplementary Tables 1 and 2

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kang, S., Nakanishi, Y., Kioi, Y. et al. Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization. Nat Immunol 19, 561–570 (2018). https://doi.org/10.1038/s41590-018-0108-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-018-0108-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing