Ly6C^high monocytes facilitate transport of Murid herpesvirus 68 into inflamed joints of arthritic mice

Abstract

Viruses, particularly the Epstein-Barr virus (EBV) has long been suspected to exacerbate acute arthritic symptoms. However, the cell populations that contribute to import viruses into the inflamed tissues remain to be identified. In the present study, we have investigated the role of monocytes in the transport of Murid herpesvirus 68 (MHV-68), a mouse virus closely related to EBV, using the serum transfer-induced arthritis (STIA) model. We found compelling evidence that MHV-68 infection markedly increased disease severity in NR4A1 mice, which are deficient for Ly6C monocytes. In contrast, the MHV-68-induced enhancement of joint inflammation was lessened in CCR2 mice, suggesting the involvement of inflammatory Ly6C monocytes in viral transport. We also observed that following selective depletion of monocyte subsets by administration of clodronate, MHV-68 transport into the synovium occurs only in the presence of Ly6C monocytes. Tracking of adoptively transferred Ly6C GFP infected monocytes into arthritic CCR2 mice by two-photon intravital microscopy showed that this monocyte subset has the capacity to deliver viruses to inflamed AR joints, as confirmed by the detection of viral DNA in inflamed tissues of recipient mice. We thus conclude that Ly6C monocytes import MHV-68 when they are mobilized to the inflamed arthritic joint.

Latent gammaherpesvirus exacerbates arthritis through modification of age-associated B cells

“…Evidence from in vivo models is scarce and previous studies have focused primarily on the direct relationship between EBV infection and damage to the joint capsule, with little attention given to systemic effects of EBV infection on immune modulation preceding and continuing throughout disease ( Kuwana et al, 2011 ; LeBel et al, 2018 ). Mice with humanized immune systems, namely NOD/Shi- scid /IL-2Rγ null mice reconstituted with CD34 + hematopoietic stem cells, that were infected with EBV went on to spontaneously develop erosive arthritis, suggesting a causative role of EBV in arthritis development ( Kuwana et al, 2011 ).…”

“…Mice with humanized immune systems, namely NOD/Shi- scid /IL-2Rγ null mice reconstituted with CD34 + hematopoietic stem cells, that were infected with EBV went on to spontaneously develop erosive arthritis, suggesting a causative role of EBV in arthritis development ( Kuwana et al, 2011 ). Related, a serum transfer‐induced arthritis model was used to demonstrate that Ly6C high monocytes play a role in transporting murine gammaherpesvirus 68 (γHV68), an EBV homolog, to the synovium ( LeBel et al, 2018 ). Our group has previously shown that latent γHV68 infection exacerbates experimental autoimmune encephalomyelitis (EAE) and leads to a disease that more closely resembles MS, with increased demyelination and infiltration of CD8 to cells of the central nervous system in γHV68-infected mice ( Casiraghi et al, 2012 ).…”

Synovial Macrophages in Rheumatoid Arthritis: The Past, Present, and Future

“…Murid herpesvirus 68 (MHV-68), a mouse virus closely related to the Epstein-Barr virus (EBV), into the inflamed joints of arthritic mice [17]. In contrast, NR4A1-dependent Ly6C lo monocytes ameliorate joint inflammation in arthritic mice through the action of Treg cells [18].…”

Latent gammaherpesvirus exacerbates arthritis and requires age-associated B cells

“…Mice with humanized immune systems, namely NOD/Shi- scid /IL-2Rγ null mice reconstituted with CD34 + hematopoietic stem cells, that were infected with EBV went on to spontaneously develop erosive arthritis, suggesting a causative role of EBV in arthritis development(16). Related, a serum transfer-induced arthritis model was used to demonstrate that Ly6C high monocytes play a role in transporting murine gammaherpesvirus 68 (γHV68), an EBV homolog, to the synovium(17). Our group has previously shown that latent γHV68 infection enhances experimental autoimmune encephalomyelitis (EAE) and leads to a disease that more closely resembles multiple sclerosis (MS)(18).…”

“…The copyright holder for this preprint this version posted February 2, 2021. ; https://doi.org/10.1101/2021.02.02.429395 doi: bioRxiv preprint 3 (gHV68), an EBV homolog, to the synovium (17). Our group has previously shown that latent gHV68 infection enhances experimental autoimmune encephalomyelitis (EAE) and leads to a disease that more closely resembles multiple sclerosis (MS)(18).…”