Obesity is a rapidly increasing global health issue, which is associated with glucose and insulin resistance. Phosphodiesterase type 5 (PDE5) inhibitors (PDE5i) are known for their ability to enhance blood flow and vascular stability and are widely used to treat conditions such as erectile dysfunction, pulmonary hypertension, heart failure, and cancer. However, studies investigating the role of PDE5i in alleviating obesity and metabolic diseases remains unclear. Therefore, we investigated the effects of PDE5i on obesity and metabolic disorders in diet-induced obese mice and its underlying mechanisms.
PDE5i was administered to high-fat diet (HFD)-fed C57BL/6J mice for 6 to 7 weeks. Body weight and food intake were measured weekly, and baseline metabolic rates, physical activity, and glucose and insulin tolerance tests were assessed during PDE5i administration. Macrophages and T-cells in the gonadal white adipose tissue (gWAT) were analyzed by flow cytometry. Vascular stability and blood flow in gWAT were analyzed via immunostaining and in vivo live imaging. RAW264.7 cells and bone marrow-derived macrophages were used to determine immunoregulatory effects of PDE5i.
In HFD-fed mice, PDE5i administration significantly enhanced systemic insulin sensitivity and AKT phosphorylation in gWAT. PDE5i reduced the M1/M2 ratio of gWAT macrophages of obese mice. These phenomena were associated with enhanced blood flow to the gWAT. In vitro experiments revealed that PDE5i suppressed lipopolysaccharide-induced proinflammatory cytokine production and increased the mRNA expression of genes associated with M2 polarization.
PDE5i plays a role in regulating adipose tissue inflammation and thus holds promise as a therapeutic agent for metabolic enhancement.

Mutations that negatively impact mitochondrial function are highly prevalent in humans and lead to disorders with a wide spectrum of disease phenotypes, including deficiencies in immune cell development and/or function. Previous analyses of mice with a hepatocyte-specific cytochrome c oxidase (COX) deficiency revealed an unexpected peripheral blood leukopenia associated with splenic and thymic atrophy. Here, we use mice with a hepatocyte-specific deletion of the COX assembly factor Sco1 to show that metabolic defects extrinsic to the hematopoietic compartment lead to a pan-lymphopenia represented by severe losses in both B and T cells. We further demonstrate that immune defects in these mice are associated with the loss of bone marrow lymphoid progenitors common to both lineages and early signs of autoantibody-mediated autoimmunity. Our findings collectively identify hepatocyte dysfunction as a potential instigator of immunodeficiency in patients with congenital mitochondrial defects who suffer from chronic or recurrent infections.
© 2025 The Author(s).

In the musculoskeletal system, lymphatic vessels (LVs), which are interdigitated with blood vessels, travel and form an extensive transport network. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, we investigate the lymphatic draining function at the tibial fracture sites using near-infrared indocyanine green lymphatic imaging (NIR-ICG) and discover that lymphatic drainage insufficiency (LDI) starts on day one and persists for up to two weeks following the fracture in male mice. Sufficient lymphatic drainage facilitates fracture healing in male mice. Furthermore, we identify that lymphatic platelet thrombosis (LPT) blocks the draining lymphoid sinus and LVs, causes LDI, and inhibits fracture healing in male mice, which can be rescued by a blood thinner. Moreover, unblocked lymphatic drainage decreases neutrophils and increases M2-type macrophages of the hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs) in male rats. Lymphatic platelet thrombolysis also benefits senile fracture healing in female mice. These findings demonstrate that LPT limits bone regeneration by impeding lymphatic transporting DAMPs. Together, these findings represent a way forward in the treatment of bone repair.
© 2025. The Author(s).

Spinal cord injury (SCI) leads to permanent motor and sensory loss that is exacerbated by intraspinal inflammation and persists months to years after injury. After SCI, monocyte-derived macrophages (MDMs) infiltrate the lesion to aid in myelin-rich debris clearance. During debris clearance, MDMs adopt a proinflammatory phenotype that exacerbates neurodegeneration and hinders recovery. The underlying cause of the lipid-mediated MDM phenotype shift is unclear. Our previous work suggests that cytosolic phospholipase A2 (cPLA2) plays a role in the proinflammatory potentiating effect of myelin on macrophages in vitro. Cytosolic phospholipase A2 (cPLA2) frees arachidonic acid from phospholipids, generating eicosanoids that play an important role in inflammation, immunity, and host defense. cPLA2 is expressed in macrophages along with multiple other cell types after SCI, and cPLA2 inhibition has been reported to both reduce and exacerbate secondary injury pathology recovery. The role of cPLA2 in MDMs after SCI is not fully understood. We hypothesize that cPLA2 activation in MDMs after SCI contributes to secondary injury. Here, we report that cPLA2 plays an important role in the myelin-induced inflammatory macrophage phenotype in vitro using macrophages derived from cPLA2 knockout bone marrow. Furthermore, to investigate the role of cPLA2 in MDMs after SCI, we generated female bone marrow chimeras using cPLA2 knock-out donors and assessed locomotor recovery using the Basso Mouse Scale (BMS), CatWalk gait analysis system, and horizontal ladder task over six weeks. We also evaluated tissue sparing and intralesional axon density six weeks after injury. cPLA2 KO chimeras did not display altered locomotor recovery or tissue pathology after SCI compared to WT chimera controls. These data suggest that although cPLA2 plays a critical role in myelin-mediated potentiation of proinflammatory macrophage activation in vitro, it may not contribute to secondary injury pathology in vivo after SCI.
© 2025. The Author(s).

Reprogramming tryptophan metabolism (TRP) may be able to overcome immunosuppression and restore the immune checkpoint blockade (ICB) response in patients with epithelial ovarian cancer (EOC) resistant to ICB therapy because TRP metabolism is involved in the kynurenine/indole and serotonin pathways of tryptophan metabolism. Herein, employing amitriptyline (AMI), an antagonist of TLR4 and serotonin transporter (SERT), we revealed that AMI remodels the immunological landscape of EOC. In particular, AMI lowered the expression of IDO1, IL-4I1, and PD-L1, the quantity of KYN and indoles, and the level of immunosuppressive immune cells MDSC, Tregs, and CD8+CD39+/PD-1+ T cell. AMI boosted the killing potential of anti-PD-1-directed CD8+T cells and worked in concert with PD-1 inhibitors to suppress tumor growth and to prolong the survival of EOC-bearing mice. This work highlights AMI as an effective regulator of ICB response by manipulating EOC cell TRP metabolism, indicating it could be a potential strategy for improving EOC ICB therapy.
© 2024 The Author(s).