It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll‐like receptors (TLRs) that respond to pathogen‐ and damage‐associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4‐mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (Bmax) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4‐blocking antibodies. We conclude that the expression, ligand‐binding capacity and pro‐inflammatory function of cardiomyocyte TLR4 are up‐regulated after long‐term MI, which promote inflammation and exacerbate heart failure.

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Mindfulness-based interventions have previously been shown to have positive effects on psychological well-being. However, the time commitment, teacher shortage, and high cost of classic mindfulness interventions may have hindered efforts to spread the associated benefits to individuals in developing countries. Brief mindfulness meditation (BMM) has recently received attention as a way to disseminate the benefits of mindfulness-based interventions. Most existing BMM methods are adaptations of the classic approach. Few studies have investigated the mechanisms underlying the beneficial effects of BMM. We developed a 15-min BMM named JW2016, which is based on the core concepts of mindfulness, Anapanasati (breath meditation of Buddhist Vipassana), our practical experience, and the results of scientific reports on meditation. We investigated the effects of this BMM on mood and emotion processing in an effort to create an effective, convenient, safe, and standardized BMM method that could benefit individuals with limited time or money to devote to meditation. Forty-six healthy participants (aged 18–25 years) were randomly allocated to the BMM group (n = 23) or the emotional regulation education (ERE) control group (n = 23). Forty-two of the study participants cooperated fully in all measurements and interventions (one time daily for seven consecutive days). Mood was measured with the Centre for Epidemiological Studies–Depression scale (CES-D) and the State Anxiety Inventory (SAI). Emotion processing was evaluated by assessing performance on an emotion intensity task, an emotional memory task, and an emotional dot-probe task. After intervention, the BMM group, but not the ERE group, showed a significant decreases in emotional intensity in response to positive as well as negative emotional stimuli, response time for emotional memory, and duration of attention bias toward negative emotional stimuli. Negative effects on mood state were found in the ERE group but not in the BMM group. This study demonstrated that BMM may improve aspects of emotion processing such as emotion intensity, emotional memory, and emotional attention bias. JW2016 BMM may be an effective, convenient, safe and standardized way to help practitioners remain focused and peaceful without any negative effect on emotion.

BackgroundDepression is one of the most common mental disorders characterized mainly by low mood and loss of interest or pleasure. About a third of patients with depression do not respond to classic antidepressant treatments. Recent evidence suggests that Mrp8/14 (myeloid-related protein 8/14) plays a crucial role in cognitive dysfunction and neuroinflammatory diseases, yet its role in mood regulation remains largely uninvestigated. In the present work, we explored the potential role of Mrp8/14 in the progression of depression.MethodsAfter 4 weeks of chronic unpredictable mild stress (CUMS), depressive-like symptoms and Mrp8/14 were determined. To verify the effects of Mrp8/14 on depressive-like behaviors, the inhibitor TAK-242 and recombinant Mrp8/14 were used. Furthermore, the molecular mechanisms in Mrp8/14-induced behavioral and biological changes were examined in vivo and ex vivo.ResultsFour-week CUMS contributed to the development of depressive symptoms. Mrp8 and Mrp14 were upregulated in the hippocampus and serum after exposure to CUMS. Pharmacological inhibition of Mrp14 attenuated CUMS-induced TLR4/NF-κB signaling activation and depressive-like behaviors. Furthermore, central administration of recombinant Mrp8, Mrp14, and Mrp8/14 resulted in neuroinflammation and depressive-like behaviors. Mrp8/14-provoked proinflammatory effects and depressive-like behaviors were improved by pretreatment with a TLR4 inhibitor. Moreover, pharmacological inhibition of TLR4 reduced the release of nitric oxide and reactive oxygen species in Mrp8/14-activated BV2 microglia.ConclusionsThese data suggest that the hippocampal Mrp8/14-TLR4-mediated neuroinflammation contributes to the development of depressive-like behaviors. Targeting the Mrp8/14 may be a novel promising antidepressant approach.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1296-0) contains supplementary material, which is available to authorized users.

Toll‐like receptors (TLRs) are essential immunoreceptors involved in host defence against invading microbes. Recent studies indicate that certain TLRs activate immunological autophagy to eliminate microbes. It remains unknown whether TLRs regulate autophagy to play a role in the heart. This study examined this question. The activation of TLR3 in cultured cardiomyocytes was observed to increase protein levels of autophagic components, including LC3‐II, a specific marker for autophagy induction, and p62/SQSTM1, an autophagy receptor normally degraded in the final step of autophagy. The results of transfection with a tandem mRFP‐GFP‐LC3 adenovirus and use of an autophagic flux inhibitor chloroquine both suggested that TLR3 in cardiomyocytes promotes autophagy induction without affecting autophagic flux. Gene‐knockdown experiments showed that the TRIF‐dependent pathway mediated the autophagic effect of TLR3. In the mouse model of chronic myocardial infarction, persistent autophagy was observed, concomitant with up‐regulated TLR3 expression and increased TLR3‐Trif signalling. Germline knockout (KO) of TLR3 inhibited autophagy, reduced infarct size, attenuated heart failure and improved survival. These protective effects were abolished by in vivo administration of an autophagy inducer rapamycin. Similar to the results obtained in cultured cardiomyocytes, TLR3‐KO did not prevent autophagic flux in mouse heart. Additionally, this study failed to detect the involvement of inflammation in TLR3‐KO‐derived protection, as wild‐type and TLR3‐KO hearts were comparable in inflammatory activity. It is concluded that up‐regulated TLR3 expression and signalling contributes to persistent autophagy following MI, which promotes heart failure and lethality.