CCR5 is a novel target for the treatment of experimental alopecia areata

Abstract

Background Alopecia areata (AA) is an organ‐specific and cell‐mediated autoimmune disease. Hair follicle autoantigens are disclosed to these autoreactive NKG2D+CD8+ T cells. A Th1 chemokine, CXCL10, is highly expressed on hair follicle keratinocytes and leads to the infiltration of CXCR3+ and CCR5+ Th1 or Tc1 cells around anagen hair follicles in AA lesions. Aim To evaluate CCR5 as a new candidate target for the treatment of experimental AA. Methods We initiated 7‐month‐old female C3H/HeJ mice with intracutaneous injections of lymph node (LN) cells, which were activated by IL‐2, IL‐7, IL‐15, and CD3/CD25 Dynabeads, from C3H/HeJ mice with spontaneous AA. Then, 330 μg/d of maraviroc, a negative allosteric modulator of the CCR5 receptor that is already used for treating patients with human immunodeficiency virus, was orally administrated for 28 days. Results We successfully treated the experimental AA lesions of C3H/HeJ mice with maraviroc. In addition, CCR5 blockade prevented the development of AA in activated T cell‐transferred C3H/HeJ mice. Interestingly, maraviroc‐treated C3H/HeJ mice with experimental AA showed improvement of hair loss lesions after 2 weeks. Immunohistological assessments and FACS analysis revealed a decreased number of CD4+CCR5+ and CD8+CCR5+ T cells in the lesions after maraviroc treatment. A real‐time horizontal chemotaxis assay showed that maraviroc significantly inhibited the chemotactic activity of CD8+ LN cells toward RANTES. Furthermore, CCR5 blockade prevented experimental AA development when compared to phosphate‐buffered saline. Conclusion CCR5 appears to be a promising new candidate target for the treatment of AA. CCR5 blockade may prevent the development of AA as well as improve AA lesions.

CCR5 promotes the migration of CD8+T cells to the leishmanial lesions

“…We found that CD8 + T cells express CCR5 preferentially at the lesions compared to the dLN. Consistent with our observation, CCR5 is mainly expressed by effector and memory CD8 + T cells [39] , [13,37,38,41], while naïve CD8 + T cells express CCR5 in a transient manner in the draining lymph node [54,55]. Also, our results show that Rag1 -/mice reconstituted with CD8 + T cells have an enrichment of CCR5 and its ligands compared to Rag1 -/mice reconstituted with CD8 + and CD4 + T cells, suggesting that this chemotactic pathway is a feature of increased pathology derived from cytolytic CD8 + T cells activity.…”

“…CCR5 also promotes the migration of memory and effector-specific CD8 + T cells to peripheral tissues and plays a beneficial role in controlling viral and toxoplasma replication in the lungs [38] and intestine [39], respectively. However, consistent with our results, CCR5 is deleterious in situations where the cytolytic activity of CD8 + T cells leads to tissue damage, for example, in cerebral malaria [37], T. cruzi-elicited cardiomyopathy [40], acute hepatitis caused by HAV infection [13], and alopecia areata [41]. In these situations, CCR5 inhibition or deletion limits CD8 + T cell-mediated pathology.…”

CCR5 promotes the migration of pathological CD8+ T cells to the leishmanial lesions

“…We found that CD8 + T cells express CCR5 preferentially at the lesions compared to the dLN. Consistent with our observation, CCR5 is mainly expressed by effector and memory CD8 + T cells [ 13 , 45 – 47 , 49 ], while naïve CD8 + T cells express CCR5 in a transient manner in the draining lymph node [ 62 , 63 ]. Also, our results show that Rag1 -/- mice reconstituted with CD8 + T cells have an enrichment of CCR5 and its ligands compared to Rag1 -/- mice reconstituted with CD8 + and CD4 + T cells, suggesting that this chemotactic pathway is a feature of increased pathology derived from cytolytic CD8 + T cells activity.…”

“…However, consistent with our results, CCR5 is deleterious in situations where the cytolytic activity of CD8 + T cells leads to tissue damage, for example, in cerebral malaria [ 45 ], T . cruzi -elicited cardiomyopathy [ 48 ], acute hepatitis caused by HAV infection [ 13 ], and alopecia areata [ 49 ]. In these situations, CCR5 inhibition or deletion limits CD8 + T cell-mediated pathology.…”

Epigallocatechin‐3‐gallate exhibits anti‐inflammatory effects in a human interface dermatitis model—implications for therapy

“…Its signalling is closely related to the inflammatory infiltration of T cells in oral LP 79 and inhibition of its receptor appears to be a promising therapeutic approach in the autoimmune skin disorder alopecia areata. 80 In LP, susceptibility of keratinocytes to T cell-mediated cytotoxic responses is increased via MHC class I induction by IFNy in a JAK2-dependent manner. 29 Interestingly, EGCG downregulates the expression of different MHC class I molecules: HLA-B, HLA-E, HLA-F, HLA-J as well as the HLA class II antigen HLA-DOB and CD74, also known as HLA-DR antigen-associated invariant chain.…”