CCL3-deficient HLA-DP2 Transgenic (Tg) mice are protected against Be-induced inflammation in the lungs

Abstract

Abstract Chronic beryllium disease (CBD) is an inflammatory lung disorder caused by the recruitment and expansion of pathogenic CD4 T cells. In a murine model of Be-disease, we reported the accumulation of CCL3/Be and CCL4/Be-specific CD4 T cells in the lungs of BeO-exposed HLA-DP2 Tg mice (WT). However, the addition of a single dose of LPS on day 14 (d14) in BeO-exposed WT mice, resulted in a significant increase in the release of chemokines (CCL3 and CCL4), increased accumulation of chemokine/Be-specific CD4 T cells and formation of cellular aggregates in the lungs. In the present study, we explored the loss of chemokine(s) CCL3/4 on the pathogenesis of CBD using HLA-DP2 Tg-CCL3-deficient mice (CCL3-DP2 Tg), which were also found to be deficient in CCL4. CCL3-DP2-Tg mice exposed to BeO+LPS (d14) caused a significant reduction in the accumulation of CCL3/4/Be-specific CD4 T cells in the lungs and the formation of cellular aggregates compared to the WT mice. Also, the ELISPOT assay revealed a significant reduction in the IFNγ and IL-17-producing CD4 T cells in the lungs of BeO-exposed CCL3-DP2-Tg mice. Next, we examined the source of CCL3 in the lungs of BeO-exposed WT mice. CCL3 is majorly contributed by CD11c +dendritic cells compared to the other cells of the hematopoietic compartment. No or little staining of CCL3 was observed in the stromal compartment. Bone marrow transfer from WT to CCL3-DP2 Tg mice showed the role of the hematopoietic compartment in both the accumulation of CCL3/4-specific CD4 T cells and the formation of cellular aggregates in the lungs after Be-exposure. Overall, we showed that hematopoietic cell-derived CCL3 or CCL4 plays an important role in the pathogenesis of CBD, and the lack of CCL3 and CCL4 protects against Be-induced lung damage. NIH RO1 HL152756