Functional remodeling of iNKT cells by sulfatide-reactive type II NKT cells reprograms alveolar macrophages to alleviate lung ischemia-reperfusion injury

Functional remodeling of iNKT cells by sulfatide-reactive type II NKT cells reprograms alveolar macrophages to alleviate lung ischemia-reperfusion injury

  • de Perrot, M., Liu, M., Waddell, T. K. & Keshavjee, S. Ischemia-reperfusion-induced lung injury. Am. J. Respir. Crit. Care Med. 167, 490–511 (2003).


    Google Scholar
     

  • Dugbartey, G. J. Therapeutic benefits of nitric oxide in lung transplantation. Biomed. Pharmacother. Biomed. Pharmacother. 167, 115549 (2023).


    Google Scholar
     

  • Xu, L. F. et al. Extracorporeal membrane oxygenation during double-lung transplantation: single center experience. Chin. Med. J. 123, 269–273 (2010).


    Google Scholar
     

  • Chacon-Alberty, L. et al. Primary graft dysfunction in lung transplantation: a review of mechanisms and future applications. Transplantation 107, 1687–1697 (2023).


    Google Scholar
     

  • Zhao, M. et al. Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury. Am. J. Physiol. Lung Cell Mol. Physiol. 291, L1018–L1026 (2006).


    Google Scholar
     

  • Locati, M., Curtale, G. & Mantovani, A. Diversity, mechanisms, and significance of macrophage plasticity. Annu. Rev. Pathol. 15, 123–147 (2020).


    Google Scholar
     

  • Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Investig. 122, 787–795 (2012).


    Google Scholar
     

  • Mahon, O. R. et al. Nano-particle mediated M2 macrophage polarization enhances bone formation and MSC osteogenesis in an IL-10 dependent manner. Biomaterials 239, 119833 (2020).


    Google Scholar
     

  • Wang, Y. H. et al. Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischaemia/reperfusion in mice. Eur. Respir. J. 61, 2200840 (2023).

  • Liu, H. et al. Efficacy of pulmonary transplantation of engineered macrophages secreting IL-4 on acute lung injury in C57BL/6J mice. Cell Death Dis. 10, 664 (2019).


    Google Scholar
     

  • Yang, J. et al. Extracellular vesicles derived from M2-like macrophages alleviate acute lung injury in a miR-709-mediated manner. J. Extracell. Vesicles 13, e12437 (2024).


    Google Scholar
     

  • Matthay, M. A. et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir. Med. 7, 154–162 (2019).


    Google Scholar
     

  • Wick, K. D., Leligdowicz, A., Zhuo, H., Ware, L. B. & Matthay, M. A. Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS. JCI Insight 6, e148983 (2021).

  • Brennan, P. J., Brigl, M. & Brenner, M. B. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat. Rev. Immunol. 13, 101–117 (2013).


    Google Scholar
     

  • Crosby, C. M. & Kronenberg, M. Tissue-specific functions of invariant natural killer T cells. Nat. Rev. Immunol. 18, 559–574 (2018).


    Google Scholar
     

  • Dasgupta, S. & Kumar, V. Type II NKT cells: a distinct CD1d-restricted immune regulatory NKT cell subset. Immunogenetics 68, 665–676 (2016).


    Google Scholar
     

  • Lu, H. et al. Potent NKT cell ligands overcome SARS-CoV-2 immune evasion to mitigate viral pathogenesis in mouse models. PLoS Pathog. 19, e1011240 (2023).


    Google Scholar
     

  • Bayatipoor, H. et al. Role of NKT cells in cancer immunotherapy-from bench to bed. Med. Oncol. 40, 29 (2022).


    Google Scholar
     

  • Halder, R. C., Aguilera, C., Maricic, I. & Kumar, V. Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease. J. Clin. Investig. 117, 2302–2312 (2007).


    Google Scholar
     

  • Arrenberg, P., Maricic, I. & Kumar, V. Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice. Gastroenterology 140, 646–655 (2011).


    Google Scholar
     

  • Yang, S. H. et al. Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury. J. Am. Soc. Nephrol. 22, 1305–1314 (2011).


    Google Scholar
     

  • Pan, H. et al. Sulfatide-activated type II NKT cells suppress immunogenic maturation of lung dendritic cells in murine models of asthma. Am. J. Physiol. Lung Cell Mol. Physiol. 317, L578–l590 (2019).


    Google Scholar
     

  • Ni, H. et al. Role of sulfatide-reactive vNKT cells in promoting lung Treg cells via dendritic cell modulation in asthma models. Eur. J. Pharmacol. 970, 176461 (2024).


    Google Scholar
     

  • Maricic, I., Halder, R., Bischof, F. & Kumar, V. Dendritic cells and anergic type I NKT cells play a crucial role in sulfatide-mediated immune regulation in experimental autoimmune encephalomyelitis. J. Immunol. 193, 1035–1046 (2014).


    Google Scholar
     

  • Lin, Q. et al. Anti-CD1d treatment suppresses immunogenic maturation of lung dendritic cells dependent on lung invariant natural killer T cells in asthmatic mice. Int. Immunopharmacol. 124, 110921 (2023).


    Google Scholar
     

  • Lombardo, L. J. et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. Journal. Med. Chem. 47, 6658–6661 (2004).


    Google Scholar
     

  • Matute-Bello, G. et al. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am. J. Respir. Cell Mol. Biol. 44, 725–738 (2011).


    Google Scholar
     

  • Sharma, A. K. et al. Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury. Am. J. Respir. Crit. Care Med. 183, 1539–1549 (2011).


    Google Scholar
     

  • Lee, Y. J. et al. Simvastatin treatment boosts benefits of apoptotic cell infusion in murine lung fibrosis. Cell Death Dis. 8, e2860 (2017).


    Google Scholar
     

  • Kechichian, T. B., Shea, J. & Del Poeta, M. Depletion of alveolar macrophages decreases the dissemination of a glucosylceramide-deficient mutant of Cryptococcus neoformans in immunodeficient mice. Infect. Immun. 75, 4792–4798 (2007).


    Google Scholar
     

  • Choi, J. P. et al. An important role of tumor necrosis factor receptor-2 on natural killer T cells on the development of dsRNA-enhanced Th2 cell response to inhaled allergens. Allergy 69, 186–198 (2014).


    Google Scholar
     

  • Wang, Y. et al. Overexpression of TIM-3 in macrophages aggravates pathogenesis of pulmonary fibrosis in mice. Am. J. Respir. Cell Mol. Biol. 61, 727–736 (2019).


    Google Scholar
     

  • Di, A. et al. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation. Immunity 49, 56–65.e54 (2018).


    Google Scholar
     

  • Menson, K. E. et al. Therapeutic efficacy of IL-17A neutralization with corticosteroid treatment in a model of antigen-driven mixed-granulocytic asthma. Am. J. Physiol. Lung Cell Mol. Physiol. 319, L693–l709 (2020).


    Google Scholar
     

  • Li, Q. & Nie, H. Advances in lung ischemia/reperfusion injury: unraveling the role of innate immunity. Inflamm. Res. 73, 393–405 (2024).


    Google Scholar
     

  • Liang, L. et al. Inhibition of YAP1 activity ameliorates acute lung injury through promotion of M2 macrophage polarization. MedComm. 4, e293 (2023).


    Google Scholar
     

  • Zhang, G. et al. Sulfatide-activated type II NKT cells prevent allergic airway inflammation by inhibiting type I NKT cell function in a mouse model of asthma. Am. J. Physiol. Lung Cell Mol. Physiol. 301, L975–L984 (2011).


    Google Scholar
     

  • Hoteit, L. et al. Macrophage switching: polarization and mobilization after trauma. Shock 59, 232–238 (2023).


    Google Scholar
     

  • Acheampong, K. K. et al. Subcellular detection of SARS-CoV-2 RNA in human tissue reveals distinct localization in alveolar type 2 pneumocytes and alveolar macrophages. mBio 13, e0375121 (2021).


    Google Scholar
     

  • Valdez, H. A. et al. Human macrophage polarization shapes B. pertussis intracellular persistence. J. Leukoc. Biol. 112, 173–184 (2022).


    Google Scholar
     

  • Kane, H. et al. Longitudinal analysis of invariant natural killer T cell activation reveals a cMAF-associated transcriptional state of NKT10 cells. eLife 11, e76586 (2022).

  • Parekh, V. V. et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Investig. 115, 2572–2583 (2005).


    Google Scholar
     

  • Bortoluzzi, S. et al. Brief homogeneous TCR signals instruct common iNKT progenitors whose effector diversification is characterized by subsequent cytokine signaling. Immunity 54, 2497–2513.e2499 (2021).


    Google Scholar
     

  • Redin, E. et al. SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation. J. Immunother. Cancer 9, e001496 (2021).

  • Wang, L. et al. Manipulation of macrophage polarization by peptide-coated gold nanoparticles and its protective effects on acute lung injury. J. Nanobiotechnol. 18, 38 (2020).


    Google Scholar
     

  • Nakamura, T. et al. Depletion of alveolar macrophages by clodronate-liposomes aggravates ischemia-reperfusion injury of the lung. J. Heart Lung Transplant. 24, 38–45 (2005).


    Google Scholar
     

  • Prakash, A. et al. Alveolar macrophages and Toll-like receptor 4 mediate ventilated lung ischemia reperfusion injury in mice. Anesthesiology 117, 822–835 (2012).


    Google Scholar
     

  • Hsiao, H. M. et al. Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β. J. Clin. Investig. 128, 2833–2847 (2018).


    Google Scholar
     

  • Liu, Y. et al. Noninvasive imaging of CCR2(+) cells in ischemia-reperfusion injury after lung transplantation. Am. J. Transplant. 16, 3016–3023 (2016).


    Google Scholar
     

  • Maus, U. A. et al. Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation: role of the CCL2-CCR2 axis. J. Immunol. 170, 3273–3278 (2003).


    Google Scholar
     

  • Zhou, P. et al. Monocytes promote pyroptosis of endothelial cells during lung ischemia-reperfusion via IL-1R/NF-κB/NLRP3 signaling. Life Sci. 276, 119402 (2021).


    Google Scholar
     

  • Patel, O. et al. Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor. Nat. Immunol. 13, 857–863 (2012).


    Google Scholar
     

  • Krijgsman, D., Hokland, M. & Kuppen, P. J. K. The role of natural killer T cells in cancer-a phenotypical and functional approach. Front. Immunol. 9, 367 (2018).


    Google Scholar
     

  • Cope, A., Le Friec, G., Cardone, J. & Kemper, C. The Th1 life cycle: molecular control of IFN-γ to IL-10 switching. Trends Immunol. 32, 278–286 (2011).


    Google Scholar
     

  • Cardone, J. et al. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat. Immunol. 11, 862–871 (2010).


    Google Scholar
     

  • Rogers, N. C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507–517 (2005).


    Google Scholar
     

  • Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).


    Google Scholar
     

  • Hu, X. et al. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 24, 563–574 (2006).


    Google Scholar
     

  • Sun, Z. et al. Exosomal circPOLQ promotes macrophage M2 polarization via activating IL-10/STAT3 axis in a colorectal cancer model. J. Immunother. Cancer 12, e008491 (2024).

  • Zhao, J., Weng, X., Bagchi, S. & Wang, C. R. Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response. Proc. Natl. Acad. Sci. USA 111, 2674–2679 (2014).


    Google Scholar
     

  • Hwang, D. et al. YAP promotes global mRNA translation to fuel oncogenic growth despite starvation. Exp. Mol. Med. 56, 2202–2215 (2024).


    Google Scholar
     

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


    Google Scholar
     

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


    Google Scholar
     

  • Han, R. et al. RAD001 (everolimus) attenuates experimental autoimmune neuritis by inhibiting the mTOR pathway, elevating Akt activity and polarizing M2 macrophages. Exp. Neurol. 280, 106–114 (2016).


    Google Scholar
     

  • Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S. & Medzhitov, R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513–519 (2017).


    Google Scholar
     

  • Li, K., Zhang, Y., Diao, Y. & Fan, S. Paeonol regulates the DDIT4-mTOR signaling pathway in macrophages to promote diabetic wound healing. Int. Immunopharmacol. 151, 114347 (2025).


    Google Scholar
     

  • Yang, H. L. et al. A defective lysophosphatidic acid-autophagy axis increases miscarriage risk by restricting decidual macrophage residence. Autophagy 18, 2459–2480 (2022).


    Google Scholar
     

  • Shi, L. et al. ETV5-mediated transcriptional repression of DDIT4 blocks macrophage pro-inflammatory activation in diabetic atherosclerosis. Cardiovasc. Toxicol. 25, 379–394 (2025).

  • Britto, F. A., Dumas, K., Giorgetti-Peraldi, S., Ollendorff, V. & Favier, F. B. Is REDD1 a metabolic double agent? Lessons from physiology and pathology. Am. J. Physiol. Cell Physiol. 319, C807–c824 (2020).


    Google Scholar
     

  • Wang, X. et al. Exosomal lncRNA HMMR-AS1 mediates macrophage polarization through miR-147a/ARID3A axis under hypoxia and affects the progression of hepatocellular carcinoma. Environ. Toxicol. 37, 1357–1372 (2022).


    Google Scholar
     

  • Ellisen, L. W. Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell Cycle 4, 1500–1502 (2005).


    Google Scholar
     

  • Bedel, R. et al. Lower TCR repertoire diversity in Traj18-deficient mice. Nat. Immunol. 13, 705–706 (2012).


    Google Scholar