<scp>JAK</scp>/<scp>STAT</scp> signaling in regulation of innate lymphoid cells: The gods before the guardians

Stabile, Helena; Scarno, Gianluca; Fionda, Cinzia; Gismondi, Angela; Santoni, Angela; Gadina, Massimo; Sciumé, Giuseppe

doi:10.1111/imr.12705

Cited by 49 publications

(32 citation statements)

References 173 publications

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“…The in vitro studies show that CXCR4 cooperatively acted with Wnt on β‐catenin signalling activation and fibrotic lesions (Figure ). Meanwhile, SDF‐1α, the ligand of CXCR4, evidently induced the phosphorylation and activation of JAK2/STAT3 and JAK3/STAT6 (Figure ), the two key effectors of signalling cascade in JAK/STAT pathways . Furthermore, overexpression of STAT3 or STAT6 repressed GSK3β transcription, and siRNA‐mediated inhibition of STAT3 or STAT6 could significantly inhibit SDF‐1α‐induced β‐catenin activation and fibrotic lesions (Figure ).…”

Section: Discussionmentioning

confidence: 96%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line to examine the expression of C-X-C motif chemokine receptor 4 (CXCR4) and β-catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up-regulated in tubules, with a concomitant activation of β-catenin. CXCR4 expression level was positively correlated with the expression of β-catenin target MMP-7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β-catenin signalling, protected against tubular injury and renal fibrosis. CXCR4-induced renal fibrosis was inhibited by treatment with ICG-001, an inhibitor of β-catenin signalling. In HKC-8 cells, overexpression of CXCR4 induced activation of β-catenin and deteriorated cell injury. These effects were inhibited by ICG-001. Stromal cell-derived factor (SDF)-1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC-8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF-1α-induced activation of β-catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β-catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades.

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Section: Discussionmentioning

confidence: 96%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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“…Similarly, several mutations have been evidenced in STATs, particularly Stat1, Stat3, and Stat5 [3,152]. Altered immune function is common to many of these mutations, including aberrant cytokine signaling and responsiveness, poor Th1 differentiation, IFN dysregulation, loss of NK cell cytotoxicity, abnormal myeloproliferation, and autoimmunity [63,152,153]. As such, many of the effects that LOF and GOF mutations in JAK-STAT pathway members direct in the cancer context are immune-associated.…”

Section: Dysregulation Of Jak-stat Signaling In Cancermentioning

confidence: 99%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

458

326

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Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.2 of 26 role in pathogenesis [3]. Yet, despite the seemingly linear order of events, the impact of mutations, selective dimerization, negative pathway regulation, and post-translational modifications of pathway members has branded the JAK-STAT axis a complex signaling cascade, of which many regulatory processes are still poorly understood.STATs have emerged as somewhat of a double-edged sword, being widely explored in the context of cancer. While several members of the STAT family, which encompasses STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 as a whole, have been linked to tumor initiation and progression (STAT3 and STAT5), others are integral in antitumor defense and the maintenance of an effective and long-term immune response (STAT1 and STAT2) through evolutionarily conserved programs [1]. With increasing emphasis on immune-based agents as important therapeutics in the fight against solid tumor growth and spread, understanding the function of STAT specificity, redundancy, and connectedness in cancer is a critical component of achieving immunotherapeutic augmentation and success.Here, we investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense. JAK-STAT Signaling and InterferonsThe presence of stimulatory or inhibitory signals governs the innate and adaptive immune activity that controls both effective immune surveillance and facilitates escape. Such signals determine the fate of plastic immune cells, such as T lymphocytes, and regulate their recruitment, survival, status, and eventual death ...

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“…The JAK-STAT pathway, and specially STAT5 action, is central for milk synthesis by mammary cells (Reichenstein et al 2011). Recent studies have also revealed that the JAK-STAT pathway is closely related to cellular immunity (Stabile et al 2018;Li et al 2019). When STAT5 was abnormally activated, it regulated the expression level of BCL-2 to change cell cycle progression and block apoptosis in several cancer cell lines (Xi et al 2003;Li et al 2005).…”

Section: Discussionmentioning

confidence: 99%

miR-122 regulates the JAK-STAT signalling pathway by down-regulating EPO in the mammary gland during Streptococcus agalactiae-induced mastitis

Chen

Chu

et al. 2020

Italian Journal of Animal Science

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MicroRNA (miRNA) are single-stranded non-coding RNA of approximately 22 nucleotides estimated to regulate 60% of human and animal genes some of which are associated with cell differentiation, signal transduction and immune processes. Streptococcus agalactiae (S. agalactiae)-induced bovine mastitis is associated with up-regulation of miR-122 and down-regulation of erythropoietin (EPO) abundance in mammary gland tissue. TargetScan analysis revealed that EPO is a predicted target gene of miR-122 and this regulatory relationship was verified by dual-luciferase reporter assay. Overexpression of miR-122 in primary bovine mammary cells led to down-regulation of EPO and also the JAK-STAT signalling pathway genes EPOR, JAK2, STAT5A and STAT5B. Accordingly, the mRNA abundance of BCL-2, a downstream gene in the JAK-STAT signalling pathway was significantly down-regulated. Under conditions of miR-122 inhibition, EPO, EPOR, JAK2, STAT5A and STAT5B were up-regulated. These results demonstrated that, through its action on EPO, miR-122 may play an important role in S. agalactiae-induced mastitis by regulating the JAK-STAT signalling pathway. HIGHLIGHTS Understanding the relationship among miR-122, EPO and the JAK-STAT pathway would be helpful in developing new strategies for controlling mastitis.

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JAK/STAT signaling in regulation of innate lymphoid cells: The gods before the guardians

Cited by 49 publications

References 173 publications

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

miR-122 regulates the JAK-STAT signalling pathway by down-regulating EPO in the mammary gland during Streptococcus agalactiae-induced mastitis

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