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Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

In this Article, the sentence: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent coding mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).", should have read: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).". This has been corrected online. In Extended Data Fig. 6a and b, which show the number of point mutations identified per sample and the mutational signatures, all sequence variants (including non-coding mutations) are shown. Fig. 2d also presents all variants compared to human mutations. In the Supplementary Information to this Amendment, we now provide the comparisons of all variants and coding variants to human mutations.

Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.

This corrects the article DOI: 10.1038/nature24302.

The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.

Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8(+) cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers. Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms. Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IκB kinase α (IKKα)-BMI1 module in prostate cancer stem cells. Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent that is effective in aggressive prostate cancer. We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.

Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies., The intestinal epithelium is the most rapidly self-renewing tissue in the mammalian body--cells have a life cycle of 3-4 days. Multiple studies have demonstrated that the intestinal stem cells (ISCs) [...]

Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic [...]

Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers (1). For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and lymphotoxin (2). But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy (3) through inhibitor of nuclear factor-κB(IκB) kinase-α (IKK-α) (4), a protein kinase that is needed for the self-renewal of mammary cancer progenitors (5) and for prostate cancer metastasis (2). We therefore examined whether RANKL, RANK and IKK-α are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that over-express the proto-oncogene Erbb2 (also known as Neu) (6), which is frequently amplified in metastatic human breast cancers (7,8), was important for pulmonary metastasis. Metastatic spread of Erbb2transformed carcinoma cells also required CD[4.sup.+]CD[25.sup.+] T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin [(SMA).sup.+] stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK1 human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD41 or FOXP31 T cells on human breast cancer prognosis9,10 and suggest that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease., RANK signalling controls osteoclastogenesis and bone resorption and has been targeted to prevent bone metastasis in breast and prostate cancers (11-13). A humanized anti-RANKL antibody seems to be a more [...]

Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma (1). Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality (2). Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12-18 months (2). Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice (3). The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth (4). Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer (5). Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK)-β and its target NF-κB have important tumour-promoting functions within malignant cells and inflammatory cells (6). The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment (7-9), but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production (10). We found that CaP progression is associated with inflammatory infiltration and activation of IKK-α, which stimulates metastasis by an NF-κB-independent, cell autonomous mechanism (11). Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-β activation results in production of cytokines that activate IKK-α and STAT3 in CaP cells to enhance hormone-free survival., To determine whether IKK-β-driven NF-κB participates in the development of castration-resistant CaP, we conditionally deleted the Ikkβ (also known as Ikbkb) gene in prostate epithelial cells of TRAMP mice, in [...]

Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours (1,2). To understand how cancer cells affect the inflammatory microenvironment, we [...]

The hypoxic response is an ancient stress response triggered by low ambient oxygen ([O.sub.2]) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose a subunit is rapidly degraded under [...]

Author(s): Etienne Meylan [1]; Jurg Tschopp (corresponding author) [1]; Michael Karin (corresponding author) [2] In an environment rich in potentially harmful microbes, survival of the host organism depends on rapidly [...]

Nuclear factor-[kappa]B (NF-[kappa]B) transcription factors and the signalling pathways that activate them are central coordinators of innate and adaptive immune responses. More recently, it has become clear that NF-[kappa]B signalling also has a critical role in cancer development and progression. NF-[kappa]B provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumour-surveillance mechanisms. NF-[kappa]B might also regulate tumour angiogenesis and invasiveness, and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches., Author(s): Michael Karin [sup.1] Author Affiliations: (1) Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine, La Jolla, USA Main A [...]

Author(s): Toby Lawrence (corresponding author) [1, 3, 4]; Magali Bebien [1, 3]; George Y. Liu [2]; Victor Nizet [2]; Michael Karin [1] Inflammation and innate immunity involve signalling pathways leading [...]

Author(s): Alok K. Sil [1]; Shin Maeda [1]; Yuji Sano [1]; Dennis R. Roop [2]; Michael Karin (corresponding author) [1] IκB kinase-α (IKK-α) [1] exhibits protein-kinase-dependent and -independent functions. Its [...]

Author(s): Li-Chung Hsu [1]; Jin Mo Park [1]; Kezhong Zhang [3]; Jun-Li Luo [1]; Shin Maeda [1]; Randal J. Kaufman [3]; Lars Eckmann [2]; Donald G. Guiney [2]; Michael Karin [...]

Author(s): Guilin Tang [1, 2]; Yuzuru Minemoto [1, 2]; Benjamin Dibling [1]; Nicole H. Purcell [1]; Zhiwei Li [3]; Michael Karin [3]; Anning Lin (corresponding author) [1] The proinflammatory cytokine [...]

Author(s): Yinling Hu [1]; Veronique Baud [1, 2, 3]; Takefumi Oga [1, 2, 3]; Keun Il Kim [1]; Kazuhiko Yoshida [1, 3]; Michael Karin (corresponding author) [1] The IKKα and [...]

Author(s): Lufen Chang; Michael Karin (corresponding author) MAPKs are evolutionary conserved enzymes connecting cell-surface receptors to critical regulatory targets within cells. MAPKs also respond to chemical and physical stresses, thereby [...]

Author(s): Yuichiro Tojima [1, 2]; Atsushi Fujimoto [1]; Mireille Delhase [3]; Yi Chen [3]; Shigetsugu Hatakeyama [4]; Kei-ichi Nakayama [4]; Yoko Kaneko [1]; Yuji Nimura [2]; Noboru Motoyama [1]; Kyoji [...]

Author(s): Antonio Rossi [1, 2]; Pankaj Kapahi [2, 3]; Gioacchino Natoli [2, 3]; Takayuki Takahashi [3]; Yi Chen [3]; Michael Karin (corresponding author) [2, 3]; M. Gabriella Santoro [1, 2, [...]

The transcription factor NF-varKappaB is activated by pro-inflammatory cytokines by the stimulation of a protein kinase, phosphorylating IvarKappaB. This leads to the translocation of freed NF-varKappaB dimers and activation of transcription of target genes, many of which code for immunoregulatory proteins. The IKK complex has been purified to homogeneity from human cell lines and it was found to comprise similar amounts of IKK-alpha, IKK-beta and two other polypeptides.

Protein kinase activity activated by tumour-necrosis factor (TNF) and phosphorylates I-kappa-B-alpha at S32/36 has been identified in extracts of TNF-treated HeLa cells. The substrate specificity and kinetics of activation were well aligned with those of phosphorylation in living cells. It was possible to determine a partial peptide sequence for one of the components of this activity, a protein kinase with associated I-kappa-B activity quickly stimulated by proinflammatory cytokines. This protein kinase, IKK-alpha, is vital for NF-kappa-B activation in the presence of proinflammatory cytokines.

All genotoxic stresses activates the p53 signalling pathway in murine fibroblasts, while Jun kinases (JNK) and c-Abl are stimulated only by specific DNA-damaging agents. Except for ultraviolet light, all stimuli activate c-Abl. The activation of c-Abl occurs in the S-phase of the cell cycle and fails to affect cell proliferation. Only ultraviolet light and methyl methanesulphonate activate JNK. The activation of JNK by the alkylating agent is normal in c-Abl-null cells and reduced in the c-Src-null cells.

The Jun proteins are characterized by near-identical sequence-recognition characteristics. A new, previously unreported Jun protein that interacts with c-Jun and JunD, but not with JunB or v-Jun, was investigated. Designated JAB-1, the new protein selectively potentiates transactivation by only c-Jun or JunD. JAB-1 does not have any effect on the binding of either JunB or v-Jun and it stabilizes complexes of c-Jun or JunD with AP-1 sites.

A newly identified protein kinase participates in the enhancement of the transcriptional activity of c-Fos by rRs through phosphorylation at Thr 232, the homologue of Ser73 of c-Jun. The protein kinase is controlled by proline, is sensitive to Ras and mitogen and is distinct from JNKS and ERKs, the other agents that mediate c-Fos transcriptional activity. Hence, three forms of proline-regulated kinases transfer the Ras and mitogen signals to the transcriptional site.

Analysis of the role of tumor suppressor p53 in DNA-damage-initiated apoptosis reveals a correlation of DNA-induced apoptosis with p53 function. The level of apoptotic DNA cleavage varies directly with p53 functional period. p53 acts either as a repressor of genes vital for cell survival or is a component of the enzymatic apparatus for apoptotic cleavage or DNA repair.

The phosphorylation of Ser 105 in the stimulation region of NF-IL6/LAP is enhanced by the activation of the protein kinase C (PKC) pathway, which also enhances the associated transcriptional effectiveness. The transactivation of cytokine and acute-stage reactant genes, in response to inflammation and infection, may be significantly influenced by the phosphorylation of NF-IL6/LAP at Ser 105 after the stimulation of the PKC pathway. In certain situations, IL-1 and lipopolysaccharide transcriptionally stimulates the NF-IL6/LAP gene, but in other cases cytokines improve their binding to cognate DNA sequences.

Author(s): Michael Karin [1] by Eric H. Davidson Elsevier: 2006. 304 pp. $69.95, £43.99 All living organisms deploy similar evolutionarily conserved mechanisms to generate energy, replicate their genomes, use genetic [...]