InVivoMAb anti-mouse CD172a (SIRPα)

Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced intramuscular fat deposition when compared with flox mice on HFD. Moreover, mSIRPα-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRPα impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRPα was upregulated in patients with DKD. In conclusion, SIRPα serves as a potential biomarker and therapeutic target in DKD.

Nuclear receptors regulate key functions of mononuclear phagocytes and are critical components of the innate immune system, acting as regulators of organ health and disease. In healthy mice, the loss of the nuclear orphan receptor NR2F6 alters tissue-resident macrophage populations in the liver, lung, and spleen. In response to Salmonella Typhimurium infection, Nr2f6-deficient mice exhibit improved clinical outcomes, characterized by reduced weight loss, bacterial loads in the spleen and liver, and decreased plasma pro-inflammatory cytokines. Despite unchanged basal iron metabolism in the spleen and liver, iron regulatory proteins and the interleukin (IL)-6-hepcidin axis are altered in Nr2f6-deficient mice during Salmonella infection, reducing hypoferremia. Transcriptomic analysis of splenic red pulp macrophages reveals significant alterations of phagocytosis-related genes, including upregulation of signal-regulatory protein alpha (Sirpa). In vitro, phagocytosis of red blood cells, regulated by the inhibitory CD47-Sirpα axis, and Salmonella Typhimurium phagocytosis are significantly impaired in Nr2f6-deficient splenic macrophages. Blocking Sirpα in vitro restores the phagocytic activity of Nr2f6-deficient macrophages to wild-type levels. In vivo, Salmonella Typhimurium loads are partially increased post-infection in anti-Sirpα treated Nr2f6-deficient mice. These findings uncover a previously unrecognized role of NR2F6 in host-pathogen interactions, positioning it as a potential therapeutic target for infectious diseases.

The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this condition has been associated with various age-associated diseases and reduced lifespan. Therefore, we investigated the role of hematopoietic LOY in promoting cellular senescence, focusing on kidney disease because of its well-documented connection with aging and senescence. Herein, a prospective cohort study revealed that LOY in blood is associated with an increased incidence of kidney diseases. Analyses of transcriptional signatures in human kidneys found that immune cell LOY is enriched in patients with kidney disease and associated with greater amounts of cellular senescence. In male mice reconstituted with bone marrow lacking the Y chromosome, renal dysfunction was accompanied by senescent cell accumulation in models of kidney injury and advanced age. Treatment with a senolytic agent promoted senolysis and preferentially inhibited the progression of renal dysfunction in LOY mice. Hematopoietic LOY led to up-regulation of multiple immune inhibitory receptors, and treatment with the combination of antibodies targeting PD-1 (programmed cell death protein 1) and SIRPα (signal regulatory protein α) reduced senescent cell accumulation and rescued the renal pathology conferred by hematopoietic LOY in the kidney injury model. Collectively, these data indicate that hematopoietic LOY contributes to pathological conditions by impairing the clearance of senescent cells through up-regulation of immune checkpoint proteins.

Tumor-infiltrating myeloid cells (TIMs) are pivotal cell populations involved in the immunosuppressive tumor immune microenvironment (TIME). However, there has been little success in large-scale clinical trials of myeloid cell modulators. We aim to investigate potential molecular targets for TIMs and disclose the underlying mechanism. Using mass cytometry by time of flight (CyTOF), we analyzed 24 spontaneous HCC tissues from mouse. Orthotopic and subcutaneous tumor models were established with or without anti-SIRPα antibody treatment. Patient-derived tumor xenografts model (PDX) was used to identify the CD47-SIRPα axis blocked therapy. In 24 murine spontaneous HCC tissues, we observed that the proportion of myeloid-derived suppressor cells (MDSCs) plus macrophages accounts for 40-90% of TIMs and SIRPα was highly expressed in TIMs, especially in macrophages and MDSCs. Through in vivo experiments, we showed that anti-SIRPα therapy inhibited tumor growth, accompanied by increased CD8+ T cells infiltration and decreased TIMs including MDSCs and macrophages. We found that anti-SIRPα inhibited immunosuppressive function, migration and PD-L1 expression of myeloid cells. In a series of in vivo experiments, we demonstrated the anti-tumor and immune-active effect of SIRPα-blocked therapy. Mechanistically, anti-SIRPα inhibited the immunosuppressive function and PD-L1 expression of TIMs through downregulating PI3K/AKT signaling in myeloid cells. At last, anti-SIRPα enhanced the antitumor effect of anti-PD-L1 therapy in orthotopic and spontaneous murine models. Together, SIRPα blocked therapy reversed the immunosuppressive TIME, which provides a promising therapeutic rationale for increasing the efficacy of anti-PD-L1 therapy in treating HCC.