Clinical evidence indicates that cognitive impairment is a common comorbidity of chronic pain, including neuropathic pain, but the mechanism underlying this comorbidity remains unclear. Neuroinflammation plays a critical role in the development of both neuropathic pain and cognitive impairment. A previous study showed that minocycline, an inhibitor of microglia, ameliorated allodynia and cognitive impairment in partial sciatic nerve ligation (PSNL) mice. Therefore, the current study examined a potential role of brain microglia in allodynia and cognitive impairment in male mice with neuropathic pain due to PSNL. Immunohistochemistry of the microglial markers ionized calcium-binding adapter molecule 1 (Iba1), transmembrane protein 119 (TMEM119), and purinergic receptor P2Y12 (P2RY12) was performed to examine microglial status. Two weeks after PSNL, significant microglial activation was observed in the hippocampus and amygdala, but not in the perirhinal cortex. Inhibition of brain-region-specific microglia with a local microinjection of clodronate liposomes was examined to elucidate the involvement of these microglia in PSNL-induced allodynia and cognitive impairment. Local clodronate liposome microinjection to the hippocampus, but not the amygdala, ameliorated allodynia and cognitive impairment. Other changes in the hippocampus of PSNL mice, e.g., decreased hippocampal dendrite length and intersections number, were prevented by microinjection of clodronate liposomes. The current findings suggest hippocampal microglia are related to cognitive impairment and allodynia through neuronal plasticity changes observed in PSNL mice. Blocking hippocampal microglia-mediated neuroinflammation may be a novel approach for reducing comorbidities such as cognitive impairment associated with neuropathic pain.

2025-05-01·Molecular Psychiatry

Adolescent social isolation decreases colonic goblet cells and impairs spatial cognition through the reduction of cystine

Article

作者: Kon, Yuki ; Ojika, Haruto ; Kagami, Akari ; Fujii, Tadashi ; Hasegawa, Masaya ; Saito, Kuniaki ; Hirooka, Yoshiki ; Tochio, Takumi ; Kosuge, Aika ; Kawai, Tomoki ; Saito, Imari ; Yoshidomi, Koyo ; Mouri, Akihiro ; Tezuka, Hiroyuki ; Kunisawa, Kazuo ; Nabeshima, Toshitaka ; Kubota, Hisayoshi ; Tanabe, Moeka

Negative experiences during adolescence, such as social isolation (SI), bullying, and abuse, increase the risk of psychiatric diseases in adulthood. However, the pathogenesis of psychiatric diseases induced by these factors remain poorly understood. In adolescents, stress affects the intestinal homeostasis in the gut-brain axis. This study determined whether adolescent SI induces behavioral abnormalities by disrupting colonic function. Adolescent mice exposed to SI exhibit spatial cognitive deficits and microglial activation in the hippocampus (HIP). SI decreased the differentiation of mucin-producing goblet cells, which was accompanied by alterations in the composition of the gut microbiota, particularly the depletion of mucin-feeding bacteria. Treatment with rebamipide, which promotes goblet cell differentiation in the colon, attenuated SI-induced spatial cognitive deficits and microglial activation in the HIP and decreased cystine, a downstream metabolite of homocysteine. Treatment with cystine ameliorated SI-induced spatial cognitive deficits and increased microglial C-C motif chemokine ligand 7 (CCL7) levels in the HIP. Inhibition of CCL7 receptors by antagonists of CC motif chemokine receptors 2 (CCR2) and 3 (CCR3) in the HIP prevented spatial cognitive deficits induced by SI. Infusion of CCL7 into the HIP following microglial ablation with clodronate liposome induced spatial cognitive deficits. These findings suggest that adolescent SI decreases serum cystine levels by damaging the colonic goblet cells, resulting in spatial cognitive deficits by triggering microglial activation in the HIP. Our results indicate that increased CCL7 expression in hippocampal microglia may contribute to spatial cognitive deficits by activating CCR2 and CCR3.

2025-05-01·Cell Biology International

Macrophage‐to‐Myofibroblast Transition Contributes to Cutaneous Scarring Formation Through the TGF‐β/Smad3 Signaling Pathways

Article

作者: Qin, Yi ; Shen, Jie‐Hong ; Yuan, Feng‐Lai ; Jia, Yuan

ABSTRACTCutaneous scarring typically arises after surgery, trauma, and infection, occurring when normal skin tissue is replaced by fibrous tissue during the healing process. Myofibroblasts have been identified as a significant contributor to this scarring. While the differentiation of fibroblasts into myofibroblasts is well‐recognized as essential for wound healing and tissue repair, the mechanisms underlying the macrophage‐myofibroblast transition (MMT) remain largely unexplored. This study aimed to investigate the role and potential mechanisms of MMT in cutaneous scarring. In specimens of hypertrophic scars, keloid and scleroderma, we confirmed the coexistence of MMT markers CD68 and α‐smooth muscle actin (α‐SMA) in areas of skin fibrosis. Additionally, most MMT cells in human cutaneous scar co‐expressed the M2‐type macrophage marker CD206. Fate‐mapping in Lyz2‐Cre/Rosa26‐tdTomato mice further demonstrated that the majority of myofibroblasts in cutaneous scars were derived from bone marrow macrophages. Furthermore, higher levels of TGF‐β were released from scar fibroblasts, which contributed to MMT through the Smad3 pathways. In vivo studies inhibiting Smad3 reduced MMT and scarring. Macrophage depletion with clodronate liposomes also reduced cutaneous scar formation. Our findings indicate that MMT plays a pivotal role in cutaneous scarring through the TGF‐β/Smad3 pathways. Consequently, inhibiting MMT may be a novel strategy for the treatment of cutaneous scarring.

100 项与 Clodronate-Liposomes 相关的药物交易

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