CXCL10 Production from Cytomegalovirus-Stimulated Microglia Is Regulated by both Human and Viral Interleukin-10

Abstract

Glial cells orchestrate immunocyte recruitment to focal areas of viral infection within the brain and synchronize immune cell functions through a regulated network of cytokines and chemokines. Since recruitment of T lymphocytes plays a critical role in resolving cytomegalovirus (CMV) infection, we investigated the production of a T-cell chemoattractant, CXCL10 (gamma interferon-inducible protein 10) in response to viral infection of human glial cells. Infection with CMV was found to elicit the production of CXCL10 from primary microglial cells but not from astrocytes. This CXCL10 expression was not dependent on secondary protein synthesis but did require the phosphorylation of p38 mitogen-activated protein (MAP) kinase. In addition, migration of activated lymphocytes toward supernatants from CMV-stimulated microglial cells was partially suppressed by anti-CXCL10 antibodies. Since regulation of central nervous system inflammation is essential to allow viral clearance without immunopathology, microglial cells were then treated with anti-inflammatory cytokines. CMV-induced CXCL10 production from microglial cells was suppressed following treatment with interleukin-10 (IL-10) and IL-4 but not following treatment with transforming growth factor ␤. The IL-10-mediated inhibition of CXCL10 production was associated with decreased CMV-induced NF-B activation but not decreased p38 MAP kinase phosphorylation. Finally, CMV infection of fully permissive astrocytes resulted in mRNA expression for the viral homologue to human IL-10 (i.e., cmvIL-10 [UL111a]) in its spliced form and conditioned medium from CMV-infected astrocytes inhibited virus-induced CXCL10 production from microglial cells through the IL-10 receptor. These findings present yet another mechanism through which CMV may subvert host immune responses.

Microglial Activation Milieu Controls Regulatory T Cell Responses

“…Although the regulation of the costimulatory molecules CD40, CD80, and CD86 was not significantly affected, there was a trend to lower CD40 transcription upon IL-10 addition. Furthermore, exogenous IL-10 resulted in a significant downregulation of the chemokine CXCL10 and IFN-g inducible NO synthase, which is in line with findings from other groups (26)(27)(28).…”

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…77,81 An analogous IL-10 homolog has not been identified in MCMV, although MCMV infection of the brain induces a strong increase in IL-10 expression (Britt WJ, 2014, unpubl. data).…”

“…75 MCMV-infected astrocytes primarily produce the chemokine CCL2, and less so, CXCL8, CCL3 and CCL5, which recruit microglial cells to the sites of infection. 76,77 Activation of microglia leads to the production of the pro-inflammatory cytokines TNF-a and IL-6 as well as chemokines CXCL10, CCL2, CCL3 and CCL5. 76,77 CXCL10 is a potent T lymphocyte chemoattractant that is critical for defense against CMV infection of the CNS.…”

“…76,77 Activation of microglia leads to the production of the pro-inflammatory cytokines TNF-a and IL-6 as well as chemokines CXCL10, CCL2, CCL3 and CCL5. 76,77 CXCL10 is a potent T lymphocyte chemoattractant that is critical for defense against CMV infection of the CNS. 78,79 Microglial cell-derived TNF-a and T cell-derived IFN-c inhibit CMV replication in astrocytes by suppressing transcription from the CMV MIEP.…”

Activating and Inhibitory Ly49 Receptors Modulate NK Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 10 and CXCL12

“…These latter chemokines are known as homeostatic chemokines. The proinflammatory chemokine CXC chemokine ligand (CXCL)10 (IFN-␥-inducible protein-10), which binds to its receptor CXCR3, is involved in certain inflammatory conditions, such as CMV and hepatitis C infections (17,18), and is reported to induce NK cell migration (19,20). CXCL12 (stromal cell-derived factor-1␣, which binds CXCR4, is a homeostatic chemokine that is chemoattractant for NK cells and may direct the homing of NK cells to the bone marrow (21,22).…”