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Background: Fibronectin (FN) can improve organ function and slow the progression of sepsis, but full-length FN is hard to be exacted as a therapeutic. Objective: This study aimed to investigate the beneficial effects of C-terminal heparin-binding domain polypeptide of FN (rhFNHC-36) in a cecal ligation and puncture (CLP)-mediated murine septic model and explore its regulatory effects on macrophages. Methods: Mice were randomly assigned to four groups: unoperated control (Normal), sham operation control (Sham), CLP-operation with intravenous injection of phosphate-buffered saline (CLP+PBS), and CLP-operation with rhFNHC-36 treatment (CLP+rhFNHC-36). Blood and abdominal fluid samples were subjected to bacterial colony formation assays. Organs (liver, spleen, and lung) were undergone histopathological analyses and/or weighed to obtain organ indices. Serum interleukin-6 (IL-6) levels, nitric oxide (NO) release from isolated abdominal macrophages, and chemotactic effect of macrophages were measured with commercial kits. Surface programmed death ligand 1 (PD-L1) expression on macrophages was measured by flow cytometry. Results: Mice in the CLP+PBS group showed a lower survival rate than that in the CLP+rhFNHC-36 group. Improved survival was associated with better clearance of bacterial pathogens, as evidenced by colony formation assays. The CLP-induced decrease in thymus and spleen indices was attenuated by rhFNHC-36 treatments. rhFNHC-36 alleviated sepsis-associated tissue damage in liver, spleen, and lung. CLP-mediated increases in plasma IL-6 levels were reversed by rhFNHC-36 treatment. NO levels in peritoneal macrophages after lipopolysaccharides (LPS)-stimulation in the CLP+rhFNHC-36 group were lower than that in the CLP+PBS group. Notably, macrophages from the CLP+rhFNHC-36 group retained better chemotaxis ability. After LPS challenge, these macrophages had a reduced percentage of PD-L1-positive cells compared to those in the CLP+PBS group. Conclusion: rhFNHC-36 improved survival of mice with CLP-induced sepsis by reducing tissue damage and modulating macrophage function. Our work provides critical insight for developing FN-based and macrophages-targeted therapeutics for treating sepsis.
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BACKGROUND: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) regulates T helper/regulatory T cell balance, autoimmunity development, and leukemia pathogenesis. As a result, this study aimed to investigate the clinical role of MALT1 in patients with acute myeloid leukemia (AML). METHODS: MALT1 expressions were measured in peripheral blood mononuclear cell (PBMC) from 90 newly diagnosed AML patients before and after induction treatment using RT-qPCR. Moreover, MALT1 expressions were also determined in 50 disease controls (DCs) and 50 healthy controls (HCs). RESULTS: MALT1 expression was reduced in AML patients compared to HCs and DCs (both adjusted P < .001). Lower MALT1 expression was related to white blood cells >10×109/L (P = .037) and poor risk stratification (P = .020) in AML patients. MALT1 expression was elevated during induction treatment not only in total AML patients (P < .001), but also in subgroups of patients achieving complete remission (CR) (P < .001) and in those not achieving CR (P = .001). Furthermore, MALT1 expressions before induction treatment (P = .042) and after induction treatment (P < .001) were both increased in AML patients with CR compared to those with non-CR. Interestingly, both pre- and post-treatment MALT1 low (vs. high) were related to shorter accumulating event-free survival (EFS), which was also associated with a reduced accumulating overall survival (OS) (all P < .05). Furthermore, MALT1 increment during induction treatment < 50% was related to unsatisfied accumulating EFS (P = .001) and OS (P = .007). CONCLUSION: PBMC MALT1 deficiency is common and relates to unfavorable induction therapy response and survival profile in AML patients.