CXCL14/BRAK: Organization of immune defense at barrier organs
Immunology
Final Report Abstract
Epithelial surfaces represent the interface between the host and the environment. They are primary entry points for pathogens and equipped with efficient anti-infectious effector programs. In the present project we demonstrated that demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function and innate host defense. Our findings in patients indicate that EGFR signaling critically regulates chemokines, antimicrobial peptides and barrier function-related proteins. Correspondingly, mice lacking epidermal EGFR (EGFRΔep) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense and deficient skin barrier function as well as early lethality. Skin toxicities were not ameliorated in a Rag2, MyD88, TNFR1 and CCL2-deficient background and also not in mice lacking epidermal Langerhans cells. Most importantly, the skin phenotype was also not rescued in a hairless (hr/hr) background demonstrating that skin inflammation is not induced by hair follicle degeneration. In addition, we could demonstrate that one of the EGFR-regulated chemokines, CXCL14, plays an important role in human cytomegalovirus infection (HCMV). Active but not UV-inactivated HCMV is capable of markedly upregulating the production of the epithelial barrier organ-associated chemokine CXCL14. Of note, this induction of CXCL14 is specific for HCMV infection, since other DNA viruses such as herpes simplex virus or vaccinia virus failed to considerably elevate expression. In addition, we show that the HCMV-associated increase in CXCL14 levels is established through a PI3K-dependent activation of the AP-1 complex. Finally, we could observe that monocytes extensively migrated in response to both HCMV-infected cells as well as recombinant CXCL14. On basis of these findings, we propose that HCMV specifically targets the chemokine CXCL14 to attract monocytes for ‘pickup’, using them as migratory vehicles for rapid dissemination within the host. Taken together, findings of the project provide important novel insights into the organization of host defense within the skin.
Publications
- (2013) Epidermal EGFR controls cutaneous host defense and prevents inflammation. Sci Transl Med. 5(199): 199ra111
Lichtenberger BM, Gerber PA, Holcmann M, Buhren BA, Amberg N, Smolle V, Schrumpf H, Boelke E, Ansari P, Mackenzie C, Wollenberg A, Kislat A, Fischer JW, Röck K, Harder J, Schröder JM, Homey B, Sibilia M
(See online at https://doi.org/10.1126/scitranslmed.3005886)
