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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.

Uyangaa E, Kim JH, Patil AM, Choi JY, Kim SB, Eo SK - PLoS Pathog. (2015)

Bottom Line: 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.Also, IFN-I signaling in HSC-derived leukocytes appeared to suppress Ly-6Ghi neutrophil recruitment to ameliorate immunopathology.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.

View Article: PubMed Central - PubMed

Affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Republic of Korea.

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.

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IFN-I–dependent cascade pathway for concerted recruitment of CD11b+Ly-6Chi monocytes and NK cells in mucosal tissues following HSV-1 infection.At the very initial phase of infection, CCL2 is initially produced from tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs through stimulation with IFN-I proteins produced from mucosal epithelium via the action of IFI-16 and STING in response to vaginal infection with HSV-1, thereby recruiting very early CD11b+Ly-6Chi monocytes within 12 h pi. Subsequently, the early infiltrated CD11b+Ly-6Chi monocytes contribute to migration-based self-amplification through the supply of higher levels of CCL2 at around 24 h pi. Delayed production of other CC chemokines (CCL3, CCL4, CCL5) from infected and uninfected epithelial cells, together with CCL2 provided by monocytes, then contributes to the recruitment of late-comer NK cells at 48 h pi. The lack of an initial CCL2 supply in IFNAR KO mice results in reduced recruitment of CD11b+Ly-6Chi monocytes; instead, CXC chemokines (CXCL1, CXCL2) primarily produced from resident cells and CD11b+Ly-6Clo monocytes probably induce massive recruitment of CD11b+Ly-6G+ neutrophils.
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ppat.1005256.g009: IFN-I–dependent cascade pathway for concerted recruitment of CD11b+Ly-6Chi monocytes and NK cells in mucosal tissues following HSV-1 infection.At the very initial phase of infection, CCL2 is initially produced from tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs through stimulation with IFN-I proteins produced from mucosal epithelium via the action of IFI-16 and STING in response to vaginal infection with HSV-1, thereby recruiting very early CD11b+Ly-6Chi monocytes within 12 h pi. Subsequently, the early infiltrated CD11b+Ly-6Chi monocytes contribute to migration-based self-amplification through the supply of higher levels of CCL2 at around 24 h pi. Delayed production of other CC chemokines (CCL3, CCL4, CCL5) from infected and uninfected epithelial cells, together with CCL2 provided by monocytes, then contributes to the recruitment of late-comer NK cells at 48 h pi. The lack of an initial CCL2 supply in IFNAR KO mice results in reduced recruitment of CD11b+Ly-6Chi monocytes; instead, CXC chemokines (CXCL1, CXCL2) primarily produced from resident cells and CD11b+Ly-6Clo monocytes probably induce massive recruitment of CD11b+Ly-6G+ neutrophils.

Mentions: CCL2 chemokine is widely studied because of its upregulation in autoimmune disease, tumors, and infections. Although CCL2 production has been shown to be regulated by TNF-α and STAT2 signals [52,53], CCL2 production can be induced by stimulation with IFN-I alone through an IFN-responsive element in the CCL2 upstream promoter [13]. Following HSV-1 mucosal infection, initial viral replication is limited to mucosa epithelium of the vaginal tract, where IFN-I is produced through the action of IFI-16/p204 and the downstream adaptor molecule STING [13,34,35,50]. This IFN-I appears to stimulate neighboring epithelial cells and tissue resident immune cells to induce the expression of CCL2 [13,50]. As another interesting finding, our data suggest the importance of vaginal tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs in providing the initial CCL2 protein responsible for recruiting early CD11b+Ly-6Chi monocytes within 12 h pi, although CD11c−EpCAM+ epithelial cells can also produce CCL2 protein through IFN-I stimulation [13,50]. It is likely that the amount of CCL2 protein produced from vaginal tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs is low, due to basally low number of these cell populations in vaginal tissue. However, the initial CCL2 may be able to recruit early CD11b+Ly-6Chi monocytes, which in turn provide more CCL2 protein to establish self-amplification of CD11b+Ly-6Chi monocyte migration. This notion is strengthened by a previous study showing that CD11b+F4/80+ macrophages in the liver provide initial CCL2 protein to recruit NK cells in a MCMV infection model [51]. The vaginal tract is composed of three principal layers: (i) the mucosa epithelium composed of stratified nonkeratinized squamous epithelial tissue, (ii) the submucosa of vascularized connective tissue, and (iii) the muscularis layer composed of smooth muscle [54]. CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs, which are responsive to stimulation by IFN-I [54], are strategically localized in both the stratified squamous epithelial layer and the submucosal lamina propria. Therefore, the data presented here suggest that IFN-I produced from initially infected epithelial cells stimulate tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs to produce initial CCL2 protein, thereby recruiting early CD11b+Ly-6Chi monocytes from the bloodstream and bone marrow within 12 h pi. Subsequently, early infiltrated CD11b+Ly-6Chi monocytes may establish migration-based self-amplification through the supply of a high amount of CCL2 protein, which peaks at around 24 h pi. Subsequently, levels of CC chemokines (CCL3, CCL4, and CCL5) produced from resident cells such as infected and uninfected epithelial cells gradually increase and peak at 48 h pi; these chemokines are responsible for the recruitment of NK cells, together with CCL2 produced by CD11b+Ly-6Chi monocytes (Fig 9). However, a lack of initial CCL2 supply from tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs in IFNAR KO mice results in diminished recruitment of CD11b+Ly-6Chi monocytes and subsequent NK cells. Instead, CXC chemokines produced from IFNAR-deficient resident cells and CD11b+Ly-6Clo monocytes is likely to induce massive recruitment of CD11b+Ly-6Ghi neutrophils into vaginal tissues.


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.

Uyangaa E, Kim JH, Patil AM, Choi JY, Kim SB, Eo SK - PLoS Pathog. (2015)

IFN-I–dependent cascade pathway for concerted recruitment of CD11b+Ly-6Chi monocytes and NK cells in mucosal tissues following HSV-1 infection.At the very initial phase of infection, CCL2 is initially produced from tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs through stimulation with IFN-I proteins produced from mucosal epithelium via the action of IFI-16 and STING in response to vaginal infection with HSV-1, thereby recruiting very early CD11b+Ly-6Chi monocytes within 12 h pi. Subsequently, the early infiltrated CD11b+Ly-6Chi monocytes contribute to migration-based self-amplification through the supply of higher levels of CCL2 at around 24 h pi. Delayed production of other CC chemokines (CCL3, CCL4, CCL5) from infected and uninfected epithelial cells, together with CCL2 provided by monocytes, then contributes to the recruitment of late-comer NK cells at 48 h pi. The lack of an initial CCL2 supply in IFNAR KO mice results in reduced recruitment of CD11b+Ly-6Chi monocytes; instead, CXC chemokines (CXCL1, CXCL2) primarily produced from resident cells and CD11b+Ly-6Clo monocytes probably induce massive recruitment of CD11b+Ly-6G+ neutrophils.
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ppat.1005256.g009: IFN-I–dependent cascade pathway for concerted recruitment of CD11b+Ly-6Chi monocytes and NK cells in mucosal tissues following HSV-1 infection.At the very initial phase of infection, CCL2 is initially produced from tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs through stimulation with IFN-I proteins produced from mucosal epithelium via the action of IFI-16 and STING in response to vaginal infection with HSV-1, thereby recruiting very early CD11b+Ly-6Chi monocytes within 12 h pi. Subsequently, the early infiltrated CD11b+Ly-6Chi monocytes contribute to migration-based self-amplification through the supply of higher levels of CCL2 at around 24 h pi. Delayed production of other CC chemokines (CCL3, CCL4, CCL5) from infected and uninfected epithelial cells, together with CCL2 provided by monocytes, then contributes to the recruitment of late-comer NK cells at 48 h pi. The lack of an initial CCL2 supply in IFNAR KO mice results in reduced recruitment of CD11b+Ly-6Chi monocytes; instead, CXC chemokines (CXCL1, CXCL2) primarily produced from resident cells and CD11b+Ly-6Clo monocytes probably induce massive recruitment of CD11b+Ly-6G+ neutrophils.
Mentions: CCL2 chemokine is widely studied because of its upregulation in autoimmune disease, tumors, and infections. Although CCL2 production has been shown to be regulated by TNF-α and STAT2 signals [52,53], CCL2 production can be induced by stimulation with IFN-I alone through an IFN-responsive element in the CCL2 upstream promoter [13]. Following HSV-1 mucosal infection, initial viral replication is limited to mucosa epithelium of the vaginal tract, where IFN-I is produced through the action of IFI-16/p204 and the downstream adaptor molecule STING [13,34,35,50]. This IFN-I appears to stimulate neighboring epithelial cells and tissue resident immune cells to induce the expression of CCL2 [13,50]. As another interesting finding, our data suggest the importance of vaginal tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs in providing the initial CCL2 protein responsible for recruiting early CD11b+Ly-6Chi monocytes within 12 h pi, although CD11c−EpCAM+ epithelial cells can also produce CCL2 protein through IFN-I stimulation [13,50]. It is likely that the amount of CCL2 protein produced from vaginal tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs is low, due to basally low number of these cell populations in vaginal tissue. However, the initial CCL2 may be able to recruit early CD11b+Ly-6Chi monocytes, which in turn provide more CCL2 protein to establish self-amplification of CD11b+Ly-6Chi monocyte migration. This notion is strengthened by a previous study showing that CD11b+F4/80+ macrophages in the liver provide initial CCL2 protein to recruit NK cells in a MCMV infection model [51]. The vaginal tract is composed of three principal layers: (i) the mucosa epithelium composed of stratified nonkeratinized squamous epithelial tissue, (ii) the submucosa of vascularized connective tissue, and (iii) the muscularis layer composed of smooth muscle [54]. CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs, which are responsive to stimulation by IFN-I [54], are strategically localized in both the stratified squamous epithelial layer and the submucosal lamina propria. Therefore, the data presented here suggest that IFN-I produced from initially infected epithelial cells stimulate tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs to produce initial CCL2 protein, thereby recruiting early CD11b+Ly-6Chi monocytes from the bloodstream and bone marrow within 12 h pi. Subsequently, early infiltrated CD11b+Ly-6Chi monocytes may establish migration-based self-amplification through the supply of a high amount of CCL2 protein, which peaks at around 24 h pi. Subsequently, levels of CC chemokines (CCL3, CCL4, and CCL5) produced from resident cells such as infected and uninfected epithelial cells gradually increase and peak at 48 h pi; these chemokines are responsible for the recruitment of NK cells, together with CCL2 produced by CD11b+Ly-6Chi monocytes (Fig 9). However, a lack of initial CCL2 supply from tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+ DCs in IFNAR KO mice results in diminished recruitment of CD11b+Ly-6Chi monocytes and subsequent NK cells. Instead, CXC chemokines produced from IFNAR-deficient resident cells and CD11b+Ly-6Clo monocytes is likely to induce massive recruitment of CD11b+Ly-6Ghi neutrophils into vaginal tissues.

Bottom Line: 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.Also, IFN-I signaling in HSC-derived leukocytes appeared to suppress Ly-6Ghi neutrophil recruitment to ameliorate immunopathology.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.

View Article: PubMed Central - PubMed

Affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, Republic of Korea.

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.

Show MeSH
Related in: MedlinePlus