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Microglia play a complex role during neurotropic virus infections; however, their role during VZV infection remains to be determined. In the present study, we explored the role of VZV-induced alterations in the morphodynamics and function of microglia in triggering neuroinflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We prepared cell-free VZV and compared replication efficiencies of wild-type (YC01) and attenuated (MAV\/06, MAV) VZV in two transformed human microglial cell lines (HMC3 and HIM) and human embryonic stem cell (ESC)-derived microglia (ESC-MG). Bulk RNA sequencing was used to assess molecular signatures of microglia following VZV infection in ESC-MG, and cytokine profiles were determined to further investigate neuroinflammation. To further examine the impact of VZV-induced microglial inflammation on neuronal responses, we generated ESC-derived sensory neurons (ESC-SN) and evaluated nociceptor expression and calcium flux as a readout for SN activities following microglial secretome treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>VZV\u00a0upregulates its gene and protein expression and triggered morphological changes in various microglia cultures. Transcriptomic analysis of YC01-infected ESC-MG revealed a robust induction of genes associated with antiviral innate immunity, alongside a pronounced upregulation of macrophage receptor with collagenous structure (MARCO). Functional studies demonstrated that MARCO facilitates VZV uptake in microglia by binding to the viral glycoprotein E (gE) via its C-terminal scavenger receptor cysteine-rich (SRCR) domain, thereby promoting viral entry and phagocytosis. Moreover, VZV infection elicited neuroinflammation in an ORF62-dependent manner, while MARCO activation triggered toll-like receptor 2 (TLR2)-mediated inflammatory signaling. This cascade further amplified the expression of pain-associated molecular mediators in an ESC-SN model, highlighting a potential mechanistic link between microglial MARCO and VZV-triggered neuropathic processes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results show, for the first time, that microglia are susceptible to VZV infection and identify MARCO as an important mediator for regulating TLR2-mediated neuroinflammation and promoting an upregulation of factors associated with neuropathic pain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01256-9","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T05:32:02Z","timestamp":1779514322000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation"],"prefix":"10.1186","volume":"33","author":[{"given":"Ji-Soo","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Jin","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Yeun","family":"Hur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subin","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seuk-Min","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael T.","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hosun","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn M. 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