Distinct Upstream Role of Type I IFN Signaling in Hematopoietic Stem Cell-Derived and Epithelial Resident Cells for Concerted Recruitment of Ly-6Chi Monocytes and NK Cells via CCL2-CCL3 Cascade

Abstract

Type I interferon (IFN-I)-dependent orchestrated mobilization of innate cells in inflamed tissues is believed to play a critical role in controlling replication and CNS-invasion of herpes simplex virus (HSV). However, the crucial regulators and cell populations that are affected by IFN-I to establish the early environment of innate cells in HSV-infected mucosal tissues are largely unknown. Here, we found that IFN-I signaling promoted the differentiation of CCL2-producing Ly-6Chi monocytes and IFN-γ/granzyme B-producing NK cells, whereas deficiency of IFN-I signaling induced Ly-6Clo monocytes producing CXCL1 and CXCL2. More interestingly, recruitment of Ly-6Chi monocytes preceded that of NK cells with the levels peaked at 24 h post-infection in IFN-I–dependent manner, which was kinetically associated with the CCL2-CCL3 cascade response. Early Ly-6Chi monocyte recruitment was governed by CCL2 produced from hematopoietic stem cell (HSC)-derived leukocytes, whereas NK cell recruitment predominantly depended on CC chemokines produced by resident epithelial cells. Also, IFN-I signaling in HSC-derived leukocytes appeared to suppress Ly-6Ghi neutrophil recruitment to ameliorate immunopathology. Finally, tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ dendritic cells appeared to produce initial CCL2 for migration-based self-amplification of early infiltrated Ly-6Chi monocytes upon stimulation by IFN-I produced from infected epithelial cells. Ultimately, these results decipher a detailed IFN-I–dependent pathway that establishes orchestrated mobilization of Ly-6Chi monocytes and NK cells through CCL2-CCL3 cascade response of HSC-derived leukocytes and epithelium-resident cells. Therefore, this cascade response of resident–to-hematopoietic–to-resident cells that drives cytokine–to-chemokine–to-cytokine production to recruit orchestrated innate cells is critical for attenuation of HSV replication in inflamed tissues.

CCL2, but not its receptor, is essential to restrict immune privileged central nervous system‐invasion of Japanese encephalitis virus via regulating accumulation of CD11b+ Ly‐6Chi monocytes

“…This speculation is based on results that decipher the detailed pathway to establish orchestrated mobilization of Ly-6C hi monocytes through CCL2 produced from HSCderived leucocytes. 55 However, it was interesting that CCL2 produced from tissue-resident cells in the CNS restrict the progression of JE because WT recipients of CCL2 KO BM donor cells (KO-WT) exhibited comparable resistance with the WT-WT BM chimeric model. Considering that CCL2 produced by resident microglia and glia cells causes the recruitment of TNF-and inducible nitric oxide synthaseexpressing macrophages and myeloid dendritic cells, 57 it is likely that CCL2 produced by resident cells may contribute to control viral dissemination in the CNS.…”

The Dual Nature of Type I and Type II Interferons

“…At sites of inflammation, type I IFNs induce production of CCL2 to recruit inflammatory monocytes ( 2 , 34 ). Type I IFN produced during vaginal HSV-1 infection induces tissue resident macrophages and DCs to produce CCL2 to recruit and initial population of inflammatory monocytes, which then enact a positive feedback loops to produce more CCL2 to attract further inflammatory monocytes ( 35 ). A similar phenomenon has been observed during vaginal HSV-2 infection, influenza infection, and inflammatory monocyte recruitment to the brain during LPS-induced systemic inflammation ( 2 , 36 , 37 ), With influenza infection, absence of IFNAR resulted in differentiation of Ly6C intermediate expressing monocytes rather than Ly6C hi inflammatory monocytes, which additionally had a different phenotype ( 36 ).…”

“…Like their monocyte counterparts, type I IFN has been implicated in NK cell recruitment to sites of inflammation. During a vaginal HSV-1 infection, type I IFN was required to induce epithelium production of CCL3, CCL4, and CCL5 to recruit NK cells to the vaginal mucosa ( 35 ). Further, type I IFN has been implicated in the activation of NK cell antiviral functions.…”

“…Type I IFN was also found to suppress pro-inflammatory NOS2+ Ly6C lo monocyte function ( 36 ). Moreover, type I IFN dampens recruitment of neutrophils by suppressing epithelial CXCL1 and CXCL2 production during virus infection ( 35 , 38 , 63 ). Not only can neutrophils produce a multitude of molecules and proteases that can promote inflammation and tissue damage, they have been shown to instigate rhinovirus-induced asthma exacerbations in mice ( 64 , 65 ).…”

Insights into the pathogenesis of herpes simplex encephalitis from mouse models

“…Infected Ifnar −/− Ifngr −/− mice, lacking both type I and II IFN receptors, exhibit high viral loads in the liver due to a failure of the IFN signaling-deficient hematopoietic compartment to control the infection (Parker et al 2016 ). For example, HSV-2 replication at the vaginal mucosa is controlled by the IFN I-dependent recruitment of cytotoxic Granzyme B + /IFNγ + NK cells and CCL2-producing Ly6C HI inflammatory monocytes; Ifnar −/− mice recruit only CXCL1/CXCL2-producing Ly6C LOW monocytes that instead promote neutrophil invasion, and fail to initiate a protective antiviral response (Uyangaa et al 2015 ). In a similar model, Ifnar −/− and Irf9 −/− mice are both more sensitive to lethal HSV-2 infection, where few IL-18-producing inflammatory monocytes are recruited to the vaginal mucosa, resulting in low IL-18-dependent production of IFNγ in NK cells (Lee et al 2017 ).…”