Abstract
CCR2 is a chemokine receptor expressed on the surface of blood leukocytes, particularly «Ly6Chi» inflammatory monocytes and microglia. Signaling through this receptor is thought to influence the immune activity of microglia as well as monocytes egress from the bone marrow (BM) and their trafficking into the central nervous system (CNS) in several neurological diseases. During experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE), CCR2 deficiency has been reported to exacerbate the outcome of the disease. However, the precise contribution of CCR2 expressed in cells of the CNS or peripheral monocytes in the protection against HSE remains unclear. To dissect the differential role of CCR2 during HSE, chimeric mice with receptor deficiency in the brain or blood cells were generated by transplanting wild-type (WT) C57BL/6 or CCR2-/- BM-derived cells in CCR2-/- (WT→CCR2-/-) and WT (CCR2-/-→WT) mice, respectively. Our results indicate that following intranasal infection with 1.2x106 plaque forming units of HSV-1, CCR2 deficiency in hematopoietic cells and, to a lesser extent, in CNS exacerbates the outcome of HSE. Mortality rates of CCR2-/- (71.4%) and CCR2-/-→WT (57.1%) mice were significantly higher than that of WT (15.3%; P<0.01 and P<0.05, respectively) but the difference did not reach statistical significance for WT→CCR2-/- animals (42.8%; P = 0.16). Both peripheral and CNS deficiencies in CCR2 resulted in increased infectious viral titers and wider dissemination of HSV antigens in the brain as well as an overproduction of inflammatory cytokines and chemokines including IL-1β, IL-6, CCL2, CCL3 and CCL5. Furthermore, CCR2 deficiency in the hematopoietic system altered monocytes egress from the BM and their recruitment to the CNS, which may contribute to the failure in HSV-1 containment. Collectively, these data suggest that CCR2 expressed on cells of CNS and especially on peripheral monocytes is important for the control of HSV-1 replication and inflammatory environment during experimental HSE.
Highlights
Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis in the Western world, accounting for up to 20% of all cases [1, 2]
It is well accepted that chemokine receptor 2 (CCR2) could be expressed by blood leukocytes including monocytes but its expression by resident microglia of the central nervous system (CNS) may vary depending on mouse models of diseases [18, 27]
CCR2-positive cells that express the microglia marker Iba1 were detected in brain sections of the olfactory bulb and the medulla of WT, CCR2-/-!WT and WT!CCR2-/- mice on days 6 (S1 Fig) and 8 post-infection (p.i.) whereas no signal was detected in CCR2-/- group
Summary
Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis in the Western world, accounting for up to 20% of all cases [1, 2]. HSE affects 2 to 4 individuals per million people per year and can result from either primary or recurrent infection mainly caused by herpes simplex virus 1 (HSV-1) [3,4,5]. HSE is known to induce severe neuro-inflammation associated with impairment of neurological functions leading to clinical signs such as altered consciousness, abnormal behavior and localized neurological findings including seizure and paralysis [6, 7]. It has been suggested that both direct virally-induced and indirect inflammatory-mediated damages are implicated in HSE and death following acute infection [9,10,11]
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