A metabolic alarmin from keratinocytes potentiates systemic humoral immunity

Lange, B. M. et al. Isoprenoid biosynthesis: the evolution of two ancient and distinct pathways across genomes. Proc. Natl Acad. Sci. USA 97, 13172–13177 (2000).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Dienz, O. et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J. Exp. Med. 206, 69–78 (2009).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sun, X. et al. Membrane-anchored CCL20 augments HIV Env-specific mucosal immune responses. Virol. J. 14, 163 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pasparakis, M. et al. Mechanisms regulating skin immunity and inflammation. Nat. Rev. Immunol. 14, 289–301 (2014).

Article  CAS  PubMed  Google Scholar 

Kashem, S. W. et al. Antigen-presenting cells in the skin. Annu. Rev. Immunol. 35, 469–499 (2017).

Article  CAS  PubMed  Google Scholar 

Kabashima, K. et al. The immunological anatomy of the skin. Nat. Rev. Immunol. 19, 19–30 (2019).

Article  CAS  PubMed  Google Scholar 

Malissen, B. et al. The origins and functions of dendritic cells and macrophages in the skin. Nat. Rev. Immunol. 14, 417–428 (2014).

Article  CAS  PubMed  Google Scholar 

Zindel, J. & Kubes, P. DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation. Annu. Rev. Pathol. 15, 493–518 (2020).

Article  CAS  PubMed  Google Scholar 

Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

Article  ADS  CAS  PubMed  Google Scholar 

Wang, X. et al. Metabolism-associated molecular patterns (MAMPs). Trends Endocrinol. Metab. 31, 712–724 (2020).

Article  CAS  PubMed  Google Scholar 

Chen, J. et al. Farnesyl pyrophosphate is a new danger signal inducing acute cell death. PLoS Biol. 19, e3001134 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Juarez, D. & Fruman, D. A. Targeting the mevalonate pathway in cancer. Trends Cancer 7, 525–540 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Okin, D. & Medzhitov, R. The effect of sustained inflammation on hepatic mevalonate pathway results in hyperglycemia. Cell 165, 343–356 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Eckert, G. P. et al. Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients. Neurobiol. Dis. 35, 251–257 (2009).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mackenzie, J. M. et al. Cholesterol manipulation by West Nile virus perturbs the cellular immune response. Cell Host Microbe 2, 229–239 (2007).

Article  CAS  PubMed  Google Scholar 

Göbel, A. et al. Cholesterol and beyond—the role of the mevalonate pathway in cancer biology. Biochim. Biophys. Acta Rev. Cancer 1873, 188351 (2020).

Article  PubMed  Google Scholar 

Yang, W. et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Luo, W. et al. SREBP signaling is essential for effective B cell responses. Nat. Immunol. https://doi.org/10.1038/s41590-022-01376-y (2022).

Bekkering, S. et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell 172, 135–146 (2018).

Article  CAS  PubMed  Google Scholar 

Zhang, M. et al. TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease. Nat. Commun. 15, 9261 (2024).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Xia, Y. et al. The mevalonate pathway is a druggable target for vaccine adjuvant discovery. Cell 175, 1059–1073 (2018).

Article  CAS  PubMed  Google Scholar 

Zhang, X. et al. Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling. Nat. Metab. 6, 2118–2137 (2024).

Article  CAS  PubMed  Google Scholar 

Hunter, C. A. & Jones, S. A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol. 16, 448–457 (2015).

Article  CAS  PubMed  Google Scholar 

Tangye, S. G. & Ma, C. S. Regulation of the germinal center and humoral immunity by interleukin-21. J. Exp. Med. 217, e20191638 (2020).

Article  PubMed  PubMed Central  Google Scholar 

Gary, E. N. et al. Mucosal chemokine adjuvant enhances synDNA vaccine-mediated responses to SARS-CoV-2 and provides heterologous protection in vivo. Cell Rep. Med. 3, 100693 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gary, E. N. & Kutzler, M. A. Defensive driving: directing HIV-1 vaccine-induced humoral immunity to the mucosa with chemokine adjuvants. J. Immunol. Res. 2018, 3734207 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Sierro, F. et al. Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells. Proc. Natl Acad. Sci. USA 98, 13722–13727 (2001).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Kayamuro, H. et al. The use of a mutant TNF-α as a vaccine adjuvant for the induction of mucosal immune responses. Biomaterials 30, 5869–5876 (2009).

Article  CAS  PubMed  Google Scholar 

Ye, L. et al. Interferon-λ enhances adaptive mucosal immunity by boosting release of thymic stromal lymphopoietin. Nat. Immunol. 20, 593–601 (2019).

Article  CAS  PubMed  Google Scholar 

Bhardwaj, N. et al. Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets. Nat. Cancer 1, 1204–1217 (2020).

Article  CAS  PubMed  Google Scholar 

Su, L. K. et al. Intranasal co-delivery of IL-6 gene enhances the immunogenicity of anti-caries DNA vaccine. Acta Pharmacol. Sin. 35, 592–598 (2014).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Tomura, M. In vivo tracking of dendritic cell migration. Methods Mol. Biol. 2618, 39–53 (2023).

Article  CAS  PubMed  Google Scholar 

Förster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).

Article  PubMed  Google Scholar 

Bang, S. et al. Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3. J. Biol. Chem. 285, 19362–19371 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Szöllősi, A. G. et al. Activation of TRPV3 regulates inflammatory actions of human epidermal keratinocytes. J. Invest. Dermatol. 138, 365–374 (2018).

Article  PubMed  Google Scholar 

Feske, S. et al. Ion channels and transporters in lymphocyte function and immunity. Nat. Rev. Immunol. 12, 532–547 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Deng, Z. et al. Gating of human TRPV3 in a lipid bilayer. Nat. Struct. Mol. Biol. 27, 635–644 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hughes, T. E. T. et al. Structural insights on TRPV5 gating by endogenous modulators. Nat. Commun. 9, 4198 (2018).

Article  ADS  PubMed  PubMed Central  Google Scholar 

Niu, C. et al. Molecular determinants for the chemical activation of the warmth-sensitive TRPV3 channel by the natural monoterpenoid carvacrol. J. Biol. Chem. 298, 101706 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sherkheli, M. A. et al. Camphor modulates TRPV3 cation channels activity by interacting with critical pore-region cysteine residues. Pak. J. Pharm. Sci. 26, 431–438 (2013).

CAS  PubMed  Google Scholar 

Qian, X. et al. IL-24 promotes atopic dermatitis-like inflammation through driving MRSA-induced allergic responses. Protein Cell 16, 188–210 (2024).

Horton, J. D. et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl Acad. Sci. USA 100, 12027–12032 (2003).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Shimano, H. & Sato, R. SREBP-regulated lipid metabolism: convergent physiology–divergent pathophysiology. Nat. Rev. Endocrinol. 13, 710–730 (2017).

Article  CAS  PubMed  Google Scholar 

Ober-Reynolds, B. et al. Integrated single-cell chromatin and transcriptomic analyses of human scalp identify gene-regulatory programs and critical cell types for hair and skin diseases. Nat. Genet. 55, 1288–1300 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hetz, C. et al. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421–438 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Celli, J. & Tsolis, R. M. Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes? Nat. Rev. Microbiol. 13, 71–82 (2015).

Article  CAS  PubMed  Google Scholar 

He, B. Viruses, endoplasmic reticulum stress, and interferon responses. Cell Death Differ. 13, 393–403 (2006).

Article  CAS  PubMed  Google Scholar 

Bahamondes Lorca, V. A. & Wu, S. Ultraviolet light, unfolded protein response and autophagy. Photochem. Photobiol. 99, 498–508 (2023).

Article  CAS  PubMed  Google Scholar 

Kozyreva, T. V. et al. The influence of TRPM8 ion channel activation on immune response at different temperature conditions. J. Therm. Biol 37, 648–653 (2012).

Article  CAS  Google Scholar 

Yamashita, H. et al. Effects of moxibustion on the enhancement of serum antibody in rabbit against Staphylococcus aureus. Am. J. Chin. Med. 26, 29–37 (1998).

Article  CAS  PubMed  Google Scholar 

Sirobhushanam, S. et al. Staphylococcus aureus colonization is increased on lupus skin lesions and is promoted by IFN-mediated barrier disruption. J. Invest. Dermatol. 140, 1066–1074 (2020).

Article  CAS  PubMed  Google Scholar 

Huang, C. et al. Disordered cutaneous microbiota in systemic lupus erythematosus. J. Autoimmun. 108, 102391 (2020).

Article  PubMed  Google Scholar 

Nakamizo, S. et al. Single-cell RNA sequencing reveals age-related changes in epidermal cell populations and interactions. J. Invest. Dermatol. 145, 1502–1505 (2025).

Article  CAS  PubMed  Google Scholar 

Zheng, M. et al. Single-cell sequencing shows cellular heterogeneity of cutaneous lesions in lupus erythematosus. Nat. Commun. 13, 7489 (2022).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Terui, H. et al. Staphylococcus aureus skin colonization promotes SLE-like autoimmune inflammation via neutrophil activation and the IL-23/IL-17 axis. Sci. Immunol. 7, eabm9811 (2022).

Article  PubMed  Google Scholar 

Klarquist, J. & Janssen, E. M. The bm12 inducible model of systemic lupus erythematosus (SLE) in C57BL/6 mice. J. Vis. Exp. https://doi.org/10.3791/53319 (2015).

Zhong, W. et al. Genotype-phenotype correlation of TRPV3-related olmsted syndrome. J. Invest. Dermatol. 141, 545–554 (2021).

Article  CAS  PubMed  Google Scholar 

Oh, D. Y. et al. Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92. J. Biol. Chem. 283, 21054–21064 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gribonika, I. et al. Skin autonomous antibody production regulates host-microbiota interactions. Nature https://doi.org/10.1038/s41586-024-08376-y (2024).

Bousbaine, D. et al. Discovery and engineering of the antibody response to a prominent skin commensal. Nature 638, 1054–1064 (2025).

Article  ADS  CAS  PubMed  Google Scholar 

Helft, J. et al. GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c+MHCII+ macrophages and dendritic cells. Immunity 42, 1197–1211 (2015).

Article  CAS  PubMed  Google Scholar 

Zhang, Y. et al. SENP3 suppresses osteoclastogenesis by de-conjugating SUMO2/3 from IRF8 in bone marrow-derived monocytes. Cell Rep. 30, 1951–1963 (2020).

Article  CAS  PubMed  Google Scholar 

Ferris, S. T. et al. cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity. Nature 584, 624–629 (2020).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Zeng, Y. et al. Substrate stiffness regulates B-cell activation, proliferation, class switch, and T-cell-independent antibody responses in vivo. Eur. J. Immunol. 45, 1621–1634 (2015).

Article  CAS  PubMed  Google Scholar 

Zhao, X. et al. Fc receptor-like 1 intrinsically recruits c-Abl to enhance B cell activation and function. Sci. Adv. 5, eaaw315 (2019).

Article  ADS  Google Scholar 

Han, Y. et al. A plant-derived TRPV3 inhibitor suppresses pain and itch. Br. J. Pharmacol. 178, 1669–1683 (2021).

Article  CAS  PubMed  Google Scholar 

Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xu, C. et al. MARCKS regulates tonic and chronic active B cell receptor signaling. Leukemia 33, 710–729 (2019).

Article  CAS  PubMed  Google Scholar 

Jiang, H. et al. Structure-based modification of an anti-neuraminidase human antibody restores protection efficacy against the drifted influenza virus. mBio 11, e02315-20 (2020).

Article  PubMed  PubMed Central  Google Scholar 

Sun, P. et al. A mosquito salivary protein promotes flavivirus transmission by activation of autophagy. Nat. Commun. 11, 260 (2020).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Chhonker, Y. et al. Simultaneous quantitation of isoprenoid pyrophosphates in plasma and cancer cells using LC-MS/MS. Molecules 23, 3275 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Yang, B. et al. An Asian-specific variant in human IgG1 represses colorectal tumorigenesis by shaping the tumor microenvironment. J. Clin. Invest. 132, e153454 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Wang, J. et al. Liver macrophages and sinusoidal endothelial cells execute vaccine-elicited capture of invasive bacteria. Sci. Transl. Med. 15, eade54 (2023).

Article  Google Scholar 

Yokogawa, M. et al. Epicutaneous application of toll-like receptor 7 agonists leads to systemic autoimmunity in wild-type mice: a new model of systemic lupus erythematosus. Arthritis Rheumatol. 66, 694–706 (2014).

Article  CAS  PubMed  Google Scholar 

Chen, X. et al. An autoimmune disease variant of IgG1 modulates B cell activation and differentiation. Science 362, 700–705 (2018).

Article  ADS  CAS  PubMed  Google Scholar 

Lu, P. et al. Ephrin B1-mediated repulsion and signaling control germinal center T cell territoriality and function. Science 356, eaai9264 (2017).

Article  PubMed  Google Scholar 

Zhang, S. et al. CD11b+CD43hiLy6Clo splenocyte-derived macrophages exacerbate liver fibrosis via spleen–liver axis. Hepatology 77, 1612–1629 (2023).

Article  PubMed  PubMed Central  Google Scholar 

Lederer, K. et al. SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation. Immunity 53, 1281–1295 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bachem, A. et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T Cells. Immunity 51, 285–297 (2019).

Article  CAS  PubMed  Google Scholar 

Starkl, P. et al. IgE effector mechanisms, in concert with mast cells, contribute to acquired host defense against Staphylococcusaureus. Immunity 53, 793–804 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173, 1083–1097 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Skopelja-Gardner, S. et al. The early local and systemic type I interferon responses to ultraviolet B light exposure are cGAS dependent. Sci. Rep. 10, 7908 (2020).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Mangiola, S. et al. tidybulk: an R tidy framework for modular transcriptomic data analysis. Genome Biol. 22, 42 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Robinson, M. D. & Oshlack, A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11, R25 (2010).

Article  PubMed  PubMed Central  Google Scholar 

Robinson, M. D. et al. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).

Article  CAS  PubMed  Google Scholar 

Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293–304 (2024).

Article  ADS  CAS  PubMed  Google Scholar 

Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Aran, D. et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 20, 163–172 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xu, S. et al. Using clusterProfiler to characterize multiomics data. Nat. Protoc. 19, 3292–3320 (2024).

Article  CAS  PubMed  Google Scholar 

Stuart, T. et al. Single-cell chromatin state analysis with Signac. Nat. Methods 18, 1333–1341 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lou, F. et al. Excessive polyamine generation in keratinocytes promotes self-RNA sensing by dendritic cells in psoriasis. Immunity 53, 204–216 (2020).

Article  CAS  PubMed  Google Scholar 

Liu, Z. et al. Analysis of myeloid cells in mouse tissues with flow cytometry. STAR Protoc. 1, 100029 (2020).

Article  PubMed  PubMed Central  Google Scholar 

Yu, X. et al. Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel. Cell Rep. 37, 110025 (2021).

Article  CAS  PubMed  Google Scholar 

Karlsson, M. et al. A single-cell type transcriptomics map of human tissues. Sci. Adv. 7, eabh2169 (2021).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Uhlen, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

Article  PubMed  Google Scholar 

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