RESUMEN
Macrophages are part of the tumor microenvironment and have been associated with poor prognosis in uveal melanoma. We determined the presence of macrophages and their differentiation status in a murine intraocular melanoma model. Inoculation of B16F10 cells into the anterior chamber of the eye resulted in rapid tumor outgrowth. Strikingly, in aged mice, tumor progression depended on the presence of macrophages, as local depletion of these cells prevented tumor outgrowth, indicating that macrophages in old mice had a strong tumor-promoting role. Immunohistochemistry and gene expression analysis revealed that macrophages carried M2-type characteristics, as shown by CD163 and peroxisome proliferator-activated receptor gamma expression, and that multiple angiogenic genes were heavily overrepresented in tumors of old mice. The M2-type macrophages were also shown to have immunosuppressive features. We conclude that tumor-associated macrophages are directly involved in tumor outgrowth of intraocular melanoma and that macrophages in aged mice have a predisposition for an M2-type profile.
Asunto(s)
Envejecimiento/inmunología , Neoplasias del Ojo/inmunología , Neoplasias del Ojo/patología , Macrófagos/inmunología , Macrófagos/patología , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Neovascularización Patológica/inmunología , Envejecimiento/patología , Animales , Línea Celular Tumoral , Polaridad Celular/inmunología , Proliferación Celular , Ácido Clodrónico/administración & dosificación , Conjuntiva/efectos de los fármacos , Conjuntiva/inmunología , Conjuntiva/patología , Modelos Animales de Enfermedad , Neoplasias del Ojo/irrigación sanguínea , Inhibidores de Crecimiento/administración & dosificación , Liposomas , Macrófagos/efectos de los fármacos , Masculino , Melanoma Experimental/irrigación sanguínea , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/patologíaRESUMEN
TLR3 recognizes dsRNAs and is considered of key importance to antiviral host-defense responses. TLR3 also triggers neuroprotective responses in astrocytes and controls the growth of axons and neuronal progenitor cells, suggesting additional roles for TLR3-mediated signaling in the CNS. This prompted us to search for alternative, CNS-borne protein agonists for TLR3. A genome-scale functional screening of a transcript library from brain tumors revealed that the microtubule regulator stathmin is an activator of TLR3-dependent signaling in astrocytes, inducing the same set of neuroprotective factors as the known TLR3 agonist polyinosinic:polycytidylic acid. This activity of stathmin crucially depends on a long, negatively charged alpha helix in the protein. Colocalization of stathmin with TLR3 on astrocytes, microglia, and neurons in multiple sclerosis-affected human brain indicates that as an endogenous TLR3 agonist, stathmin may fulfill previously unsuspected regulatory roles during inflammation and repair in the adult CNS.