Haiyan Zhou

Pulmonary fibrosis (PF) is sexually dimorphic, with a relatively high prevalence and severity in males; however, the mechanism remains unclear. Our study revealed pronounced sexual dimorphism of immune cell genes in the lung, among which grancalcin (GCA) showed profound sex differences. GCA was produced by lung-infiltrating bone marrow macrophages triggered by heightened inflammation in the lung. However, a unique HTR2C⁺ alveolar macrophage population enriched in female lungs metabolically reprogramed bone marrow-derived macrophages and constrained local GCA amplification. As a novel chemokine, GCA bound to protein tyrosine phosphatase receptor type T (PTPRT) in Th17 cells and facilitated pathogenic lung infiltration by activating the ROCK1-MLC pathway, thus aggravating lung fibrosis. Notably, both GCA and Th17 cells abundantly accumulated in lung biopsies from male PF patients but not in those from female patients. GCA-neutralizing antibodies in combination with pirfenidone, a prescribed medication for treating fibrosis, provided superior effectiveness and survival rates against PF compared with treatment with pirfenidone alone. Overall, our findings reveal that sex-biased lung fibrosis is shaped by lung immune-regulatory units, which could be targeted to limit lung fibrosis.

Chronic diabetic wounds are a serious complication of diabetes and often result in limb amputations and confer high mortality rates. The proinflammatory secretome in the wound perpetuates defective neovascularization and contributes to dysregulated tissue repair. This study aims to design a gelatin methacrylamide (GelMA) hydrogel to sustained the release of grancalcin‐neutralizing antibody (GCA‐NAb) and evaluate it as a potential scaffold to promote diabetic wound healing. Results show that the expression of grancalcin(GCA), a protein secreted by bone marrow‐derived immune cells, is elevated in the wound sites of individuals and animals with diabetic ulcers. Genetic inhibition of grancalcin expression accelerates vascularization and healing in an animal model. Mechanistic studies show that grancalcin binds to transient receptor potential melastatin 8(TRPM8) and partially inactivates its downstream signaling pathways, thereby impairing angiogenesis in vitro and ex vivo. Systemic or topical administration of a GCA‐NAb accelerate wound repair in mice with diabetes. The data suggest that GCA is a potential therapeutic target for the treatment of diabetic ulcers.

The crosstalk between the bone and adipose tissue is known to orchestrate metabolic homeostasis, but the underlying mechanisms are largely unknown. Herein, we find that GCA + (grancalcin) immune cells accumulate in the bone marrow and release a considerable amount of GCA into circulation during obesity. Genetic deletion of Gca in myeloid cells attenuates metabolic dysfunction in obese male mice, whereas injection of recombinant GCA into male mice causes adipose tissue inflammation and insulin resistance. Mechanistically, we found that GCA binds to the Prohibitin-2 (PHB2) receptor on adipocytes and activates the innate and adaptive immune response of adipocytes via the PAK1-NF-κB signaling pathway, thus provoking the infiltration of inflammatory immune cells. Moreover, we show that GCA-neutralizing antibodies improve adipose tissue inflammation and insulin sensitivity in obese male mice. Together, these observations define a mechanism whereby bone marrow factor GCA initiates adipose tissue inflammation and insulin resistance, showing that GCA could be a potential target to treat metainflammation.

Alzheimer's disease (AD) is an age‐related degenerative disease of the central nervous system (CNS), whereas the role of bone marrow immune cells in the pathogenesis of AD remains unclear. Here, the study reveals that compared to matched healthy individuals, AD patients have higher circulating grancalcin (GCA) levels, which negatively correlate with cognitive function. Bone marrow‐derived GCA⁺ immune cells, which secret abundant GCA and increase during aging, preferentially invaded the hippocampus and cortex of AD mouse model in a C‐C Motif Chemokine Receptor 10 (CCR10)‐dependent manner. Transplanting GCA⁺ immune cells or direct stereotaxic injection of recombinant GCA protein intensified amyloid plaque load and aggravated cognitive and memory impairments. In contrast, genetic ablation of GCA in the hematopoietic compartment improves cognitive and memory function. Mechanistically, GCA competitively binds to the low‐density lipoprotein receptor‐related protein 1 (LRP1) in microglia, thus inhibiting phagocytosis and clearance of Aβ and potentiating neuropathological changes. Importantly, GCA‐neutralizing antibody treatment rejuvenated cognitive and memory function and constrained AD progression. Together, the study demonstrates a pathological role of GCA⁺ immune cells instigating cognitive and memory decline, suggesting that GCA⁺ immune cells can be a potential target for innovative therapeutic strategies in AD.

Thermogenesis in brown adipose tissue (BAT) declines with aging, however, the underlying mechanism remains unclear. Here, we show that the expression of Y‐box binding protein 1 (YB‐1), a critical DNA/RNA binding protein, decreased in the BAT of aged mice due to the reduction of microbial metabolite butyrate. Genetic ablation of YB‐1 in the BAT accelerated diet‐induced obesity and BAT thermogenic dysfunction. In contrast, overexpression of YB‐1 in the BAT of aged mice was sufficient to promote BAT thermogenesis, thus alleviating diet‐induced obesity and insulin resistance. Interestingly, YB‐1 had no direct effect on adipose UCP1 expression. Instead, YB‐1 promoted axon guidance of BAT via regulating the expression of Slit2, thus potentiating sympathetic innervation and thermogenesis. Moreover, we have identified that a natural compound Sciadopitysin, which promotes YB‐1 protein stability and nuclear translocation, alleviated BAT aging and metabolic disorders. Together, we reveal a novel fat‐sympathetic nerve unit in regulating BAT senescence and provide a promising strategy against age‐related metabolic disorders.

Large temperature difference is reported to be a risk factor for human health. However, little evidence has reported the effects of temperature fluctuation on sarcopenia, a senile disease characterized by loss of muscle mass and function. Here, we demonstrate that higher diurnal temperature range in humans has a positive correlation with the prevalence of sarcopenia. Fluctuated temperature exposure (10–25 °C) accelerates muscle atrophy and dampens exercise performance in mid-aged male mice. Interestingly, fluctuated temperature alters the microbiota composition with increased levels ofParabacteroides_distasonis,Duncaniella_dubosiiand decreased levels ofCandidatus_Amulumruptor,Roseburia,Eubacterium. Transplantation of fluctuated temperature-shaped microbiota replays the adverse effects on muscle function. Mechanically, we find that altered microbiota increases circulating aminoadipic acid, a lysine degradation product. Aminoadipic acid damages mitochondrial function through inhibiting mitophagy in vitro. AndEubacteriumsupplementation alleviates muscle atrophy and dysfunction induced by fluctuated temperature. Our results uncover the detrimental impact of fluctuated temperature on muscle function and provide a new clue for gut-muscle axis.

Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8 ⁺ immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8 ⁺ immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks. Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit adipose RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function. Xenotransplantation experiments show that human S100A8 ⁺ immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.

Mucosal healing is a key treatment goal for inflammatory bowel disease, and adequate epithelial regeneration is required for an intact gut epithelium. However, the underlying mechanism for mucosal healing is unclear. Long noncoding RNAs (lncRNAs) have been reported to be involved in the development of inflammatory bowel disease. Here, we report that a lncRNA named Gm31629 decreased in intestinal epithelial cells in response to inflammatory stimulation. Gm31629 deficiency led to exacerbated intestinal inflammation and delayed epithelial regeneration in dextran sulfate sodium–induced (DSS-induced) colitis model. Mechanistically, Gm31629 promoted E2F pathways and cell proliferation by stabilizing Y-box protein 1 (YB-1), thus facilitating epithelial regeneration. Genetic overexpression of Gm31629 protected against DSS-induced colitis in vivo. Theaflavin 3-gallate, a natural compound mimicking Gm31629, alleviated DSS-induced epithelial inflammation and mucosal damage. These results demonstrate an essential role of lncRNA Gm31629 in linking intestinal inflammation and epithelial cell proliferation, providing a potential therapeutic approach to inflammatory bowel disease.