Date Published: November 30, 2015
Publisher: Public Library of Science
Author(s): Erdenebileg Uyangaa, Jin Hyoung Kim, Ajit Mahadev Patil, Jin Young Choi, Seong Bum Kim, Seong Kug Eo, Pinghui Feng.
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.
Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are significant human pathogens and the most common cause of genital ulceration in humans worldwide [1,2]. Typically, infection with HSV-1 or -2 via genital routes results in a lifelong latent infection of the host after peripheral replication in mucosal tissues , thereby providing potential transmission to neighbor hosts in response to reactivation. In addition, acquisition of human immunodeficiency virus (HIV) is increased 2- to 3-fold in HSV-infected individuals, underscoring the contribution of this virus in facilitating increased susceptibility to other microbial pathogens [4–6]. Consequently, it is imperative to characterize the host defense to HSV infection and identify key components that regulate virus resistance in order to devise a strategy that will reduce viral prevalence.
Although extensive studies have focused on the antiviral nature of IFN-I, its role in the generation of innate immune cells derived from HSC lineages was only recently described. In particular, IFN-I signaling appears to be critical for the recruitment and activation of innate immune cells, including CD11b+Ly-6Chi monocytes and NK cells, in inflammatory tissues [29,30]. However, the critical regulators of IFN-I–dependent recruitment of CD11b+Ly-6Chi monocytes and NK cells and their cellular source were not defined. Our data show that IFN-I signals govern the recruitment and activation of CD11b+Ly-6Chi and NK cells, which is associated with susceptibility to HSV-1 mucosal infection. An intriguing finding is that the sequential recruitment of CD11+Ly-6Chi monocytes and then NK cells into mucosal tissue appears to depend on the CCL2-CCL3 cascade mediated by HSC-derived leukocytes and resident cells, respectively. Furthermore, tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs were involved in producing the initial CCL2 for migration-based self-amplification of rapidly infiltrated CD11b+Ly-6Chi monocytes through stimulation by IFN-I produced from infected epithelial cells. To the best of our knowledge, this is the first report that deciphers the cellular and molecular cascade pathway to regulate IFN-I-dependent recruitment of CD11b+Ly-6Chi monocytes and NK cells into inflammatory mucosal tissues.