RESUMEN

Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.

RESUMEN

Multiple myeloma (MM) tumour cells evade host immunity through a variety of mechanisms, which may potentially include the programmed cell death ligand-1 (PD-L1):programmed cell death protein-1 (PD-1) axis. This interaction contributes to the immunosuppressive bone marrow (BM) microenvironment, ultimately leading to reduced effector cell function. PD-L1 is overexpressed in MMBM and is associated with the resistance to immune-based approaches for treating MM. Ruxolitinib (RUX), an inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases, is approved for myeloproliferative diseases. We investigated the effects of RUX alone or in combination with anti-MM agents on the expression of PD-L1 and T-cell cytotoxicity in MM. We showed that the expression of the PD-L1 gene was markedly increased in BM mononuclear cells from patients with MM with progressive disease versus those in complete remission. Furthermore, RUX treatment resulted in a concentration-dependent reduction of PD-L1 gene expression in the MM tumour cells cultured alone or co-cultured with stromal cells compared with untreated cells. The results also demonstrated that RUX increased MM cell apoptosis in the presence of interleukin-2-stimulated T cells to a similar degree as the treatment with anti-PD-1 or anti-PD-L1 antibodies. In summary, these results indicate that RUX can block PD-L1 expression resulting in augmentation of anti-MM effects of T cells.

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RESUMEN

While the incidence and risk factors of pulmonary embolism (PE) and deep vein thrombosis (DVT) following spinal surgery have been well studied, the treatment of such thromboembolic disease in patients after spine surgery remains controversial. When initiating therapeutic anticoagulation after spine surgery, clinicians must weigh the catastrophic risk of a PE against the risk of bleeding complications associated with anticoagulation therapy. Here we report the case of a 56-year-old male who presented with symptoms of spinal cord compression secondary to metastatic renal cell carcinoma (RCC). An inferior vena cava (IVC) filter was inserted preoperatively and urgent decompression at the thoraco-lumbar region was performed. Therapeutic clexane was started on postoperative day (POD) 7 and he was discharged. On POD 8, he was readmitted following acute bilateral lower limb paralysis. Magnetic resonance imaging (MRI) revealed a large posterior spinal epidural hematoma with severe compression of the conus at L1 level. Urgent posterior decompression was performed but subsequent recovery was slow and incomplete. His power improved gradually over the right lower limb with attainment of grade 4/5 motor power but still had hemiparesis on his left lower limb upon discharge out of hospital. This case highlights the risk of starting therapeutic anticoagulation following spinal surgery. Prior to starting treatment, the clinician must consider the appropriate dose, timing and alternatives available to avoid unnecessary complications.