Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4 -/-) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4 -/-mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4 -/-mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4 -/-mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4 -/-mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4 -/-mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon.

Objectives: Ischemia-reperfusion injury (IRI) is a major cause of chronic renal fibrosis.Currently, numerous therapies have shown a minimal effect on the blockade of fibrosis progression. Here, the therapeutic potential of peptide-based TGF-β1 inhibitor P144 in IRI-induced renal fibrosis and the underlying mechanism were analyzed. Materials and Methods: The unilateral ischemia-reperfusion injury with the contralateral nephrectomy model was established, and the P144 was administered intravenously 1d/14d after the onset of IRI. The histopathology and immunofluorescence staining were used to detect renal fibrosis and macrophage infiltration. The in vivo fluorescence imaging was used to measure the bio-distribution of P144. The transwell assays were used to observe the migration of macrophages. RT-qPCR and western blot were used to analyze TGF-β1 signaling. Results: P144 ameliorated the accumulation of extracellular matrix in the kidney and improved the renal function in the unilateral ischemia-reperfusion injury plus contralateral nephrectomy model. Mechanistically, P144 downregulated the TGF-β1-Smad3 signaling at both the transcriptional and translational levels and further reduced the TGF-β1-dependent infiltration of macrophages to the injured kidney. Additionally, P144 blocked the polarization of macrophages to an M2-like phenotype induced by TGF-β1 in vitro, but showed no effect on their proliferation. Conclusions: Our study showed that the TGF-β1 peptide-based inhibitor P144 decreased renal fibrosis through the blockade of the TGF-β1-Smad3 signaling pathway and the modulation of macrophage polarization, suggesting its potential therapeutic use in IRI-induced renal fibrosis. Delun Li and Jian Zhang contributed equally as co-first authors.

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