Role Of Follistatin-like Protein 1 Research Articles

FSTL1-knockdown improves neural oscillation via decreasing neuronal-inflammation regulating apoptosis in Aβ1–42 induced AD model mice

Follistatin like protein 1 (FSTL1) is a famous growth regulatory protein. FSTL1 has been noticed in many diseases, including heart and lung ischemia, cerebral ischemia, glioma, schizophrenia, and Autism. The role of FSTL1 has been declared in the genetics and development of the central nervous system. Therefore, we designed this study to investigate the function and the role of FSTL1 in Alzheimer's disease. Firstly, we noticed upregulated expression level of FSTL1 among four to six-month-old 5XFAD AD mice. Accordingly, we hypothesized that FSTL1-Knockdown improved AD model mice's cognitive function and recover from Alzheimer's disease. Thus, AD model mice were made by single intracerebroventricular injections of Aβ1–42 peptides in FSTL1+/− and CON mice. Next, our results concluded that FSTL1-knockdown effectively improved cognitive functions. FSTL1-knockdown enhanced the pattern of neural oscillations, and synaptic plasticity in Aβ1–42 treated FSTL1-Knockdown mice compared to Aβ1–42 induced AD model mice. Next, FSTL1-Knockdown inhibited the activation of microglia and binding of TLR-4 with microglia. Further, inactivated microglia stopped the formation of MyD88. Thus, our data revealed that FSTL1-Knockdown is slowing down the caspase/BAX/Bcl-2/TLR-4 regulating apoptosis pathway, and the expression of inflammatory cytokines in the hippocampus of Aβ1–42 inserted FSTL1-Knockdown mice. Overall, all these data illuminate the clinical significance role of down-regulated FSTL1. FSTL1-Knockdown reduced the amyloid-beta by affecting microglia, neural-inflammation and apoptosis in AD-like model mice. Finally, down regulation of FSTL1 improved synaptic plasticity, neural oscillations, and cognitive behaviours in the Aβ1–42 induced AD model mice.

Knockdown of FSTL1 inhibits microglia activation and alleviates depressive-like symptoms through modulating TLR4/MyD88/NF-κB pathway in CUMS mice

Inflammatory processes play a pivotal role in the development and progression of depression. Since Follistatin-like protein 1 (FSTL1) has been identified as a novel inflammatory protein, a variety of studies suggest that targeting FSTL1 may be useful in the treatment of diseases in which inflammation plays a central role. In the study, we aimed to investigate the causal relationship between FSTL1 signaling and the development of depression. To explore the effect and mechanism of FSTL1 on chronic stress-induced depression, the chronic unpredictable mild stress (CUMS) paradigm was used. Animals subjected to CUMS for 4 weeks exhibited depressive-like symptoms, including decreased sucrose preference and obvious behavioral despair, concomitantly with increased FSTL1 level in the hippocampus. In contrast, mice with FSTL1 knockdown abolished CUMS induced depression-like and anxiety-like behaviors. Moreover, FSTL1 knockdown reversed CUMS induced synaptic plasticity deficits in the PP-DG pathway of the hippocampus and increased the expression of synaptic associated proteins in the hippocampus of CUMS exposed mice. Microglia activation induced by CUMS paradigm could be significantly inhibited by FSTL1 knockdown. Furthermore, Western blot revealed that FSTL1 knockdown considerably decreased the expression of indicated molecules TLR4/MyD88/NF-κB signaling pathway in CUMS exposed mice. In conclusion, our data implies that FSTL1 may modulate the microglial activation through TLR4/MyD88/NF-κB signaling, which affects depression-like behaviors and synaptic function deficits induced by CUMS in mice. These results suggested that the role of FSTL1 in mediating microglia-related mechanisms in depression may shed light on developing new therapeutic strategies to treat this prevalent disease.

FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

BackgroundCigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling.MethodsSerum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed.ResultsBoth FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice.ConclusionsFSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

Regulation of Pulmonary Bacterial Immunity by Follistatin-Like Protein 1.

Klebsiella pneumoniae is a common cause of antibiotic-resistant pneumonia. Follistatin-like protein 1 (FSTL-1) is highly expressed in the lung and is critical for lung homeostasis. The role of FSTL-1 in immunity to bacterial pneumonia is unknown. Wild-type (WT) and FSTL-1 hypomorphic (Hypo) mice were infected with Klebsiella pneumoniae to determine infectious burden, immune cell abundance, and cytokine production. FSTL-1 Hypo/TCRδ-/- and FSTL-1 Hypo/IL17ra-/- were also generated to assess the role of γδT17 cells in this model. FSTL-1 Hypo mice had reduced K. pneumoniae lung burden compared with that of WT controls. FSTL-1 Hypo mice had increased Il17a/interleukin-17A (IL-17A) and IL-17-dependent cytokine expression. FSTL-1 Hypo lungs also had increased IL-17A+ and TCRγδ+ cells. FSTL-1 Hypo/TCRδ-/- displayed a lung burden similar to that of FSTL-1 Hypo and reduced lung burden compared with the TCRδ-/- controls. However, FSTL-1 Hypo/TCRδ-/- mice had greater bacterial dissemination than FSTL-1 Hypo mice, suggesting that gamma delta T (γδT) cells are dispensable for FSTL-1 Hypo control of pulmonary infection but are required for dissemination control. Confusing these observations, FSTL-1 Hypo/TCRδ-/- lungs had an increased percentage of IL-17A-producing cells compared with that of TCRδ-/- mice. Removal of IL-17A signaling in the FSTL-1 Hypo mouse resulted in an increased lung burden. These findings identify a novel role for FSTL-1 in innate lung immunity to bacterial infection, suggesting that FSTL-1 influences type-17 pulmonary bacterial immunity.

Follistatin like protein-1 modulates macrophage polarization and aggravates dextran sodium sulfate-induced colitis

Follistatin-like protein 1 (FSTL1) is a pleiotropic cytokine involved in multiple processes including organ development, carcinogenesis, metastasis and so on. Some recent studies have suggested a possible role of FSTL1 in the inflammatory diseases. We for the first time tried to unravel its effect on the colitis, and explore the possible mechanisms. Here we found that FSTL1 was upregulated in active human and murine colitis. It facilitated proinflammatory M1 polarization of macrophages and inhibited the M2 anti-inflammatory phenotype, leading to excessive production of multiple inflammatory cytokines in vitro and in vivo. Haplodeletion of FSTL1 in mice significantly reduced the clinical and histological activity of colitis. Most importantly, macrophage depletion diminished the difference between DSS-treated WT and FSTL1+/− mice. Altogether, our results suggested that FSTL1 may also serve as an important contributor in the colonic inflammation. The possible mechanism may be related to its modulation on macrophage polarization.

Determination of follistatin-like protein 1 expression in colorectal cancer and its association with clinical outcomes.

Follistatin-like protein 1 (FSTL1) has been demonstrated to play a controversial role in cancer. In this study, we aimed to investigate the expression of FSTL1 and its characteristics in patients with colorectal cancer (CRC). Gene expression microarray assays in 30 CRC patients and a real-time quantitative polymerase chain reaction (RT-qPCR) of 22 patients were performed to compare the mRNA level of FSTL1 in tumor lesions and paired normal tissues. Also, 332 consecutive patients with pathologically confirmed CRC were selected to detect FSTL1 expression by using immunohistochemistry (IHC). Enzyme-linked immunosorbent assay (ELISA) was also applied to determine the serum level of FSTL1 in 60 CRC patients, as well as 34 healthy donors. Gene expression microarray assays and RT-qPCR in CRC tissues, as well as ELISA in the serum all, revealed that the expression level of FSTL1 was higher in cancer tissue of CRC patients compared with paired normal tissue or healthy donors. The IHC results suggested that FSTL1 was also higher in tumor tissues than in its normal counterparts, however interestingly, a narrow scan focusing on the stromal region indicated that FSTL1 was significantly higher in normal tissues than in cancerous tissues. Besides, higher FSTL1 expression in cancer tissue, as well as lower FSTL1 expression in cancer stroma, both correlated with a worse prognosis, and the latter was an independent prognostic factor. Our results provide novel insight into the role of FSTL1 in CRC, and it might be an essential factor in CRC development.