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

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. © 2015 uyangaa et al.