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Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality
Author(s) -
Adebiyi Morayo G.,
Zhao Zhaoyang,
Ye Youqiong,
Manalo Jeanne,
Hong Yue,
Lee Cheng Chi,
Xian Wa,
McKeon Frank,
CulpHill Rachel,
D'Alessandro Angelo,
Kellems Rodney E.,
Yoo SeungHee,
Han Leng,
Xia Yang
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900246rr
Subject(s) - per1 , per2 , inflammation , circadian rhythm , medicine , endocrinology , immunology , biology , circadian clock , clock
The circadian clock is important for cellular and organ function. However, its function in sickle cell disease (SCD), a life‐threatening hemolytic disorder, remains unknown. Here, we performed an unbiased microarray screen, which revealed significantly altered expression of circadian rhythmic genes, inflammatory response genes, and iron metabolic genes in SCD Berkeley transgenic mouse lungs compared with controls. Given the vital role of period 2 (Per2) in the core clock and the unrecognized role of Per2 in SCD, we transplanted the bone marrow (BM) of SCD mice to Per2 Luci f erase mice, which revealed that Per2 expression was up‐regulated in SCD mouse lung. Next, we transplanted the BM of SCD mice to period 1 ( Per1 ) /Per2 double deficient [ Per1/Per2 double knockout (dKO )] and wild‐type mice, respectively. We discovered that Per1/Per2 dKO mice transplanted with SCD BM (SCD → Per1/Per 2 dKO ) displayed severe irradiation sensitivity and were more susceptible to an early death. Although we observed an increase of peripheral inflammatory cells, we did not detect differences in erythrocyte sickling. However, there was further lung damage due to elevated pulmonary congestion, inflammatory cell infiltration, iron overload, and secretion of IL‐6 in lavage fluid. Overall, we demonstrate that Per1/Per 2 is beneficial to counteract elevated systemic inflammation, lung tissue inflammation, and iron overload in SCD.—Adebiyi, M. G., Zhao, Z., Ye, Y., Manalo, J., Hong, Y., Lee, C. C., Xian, W., McKeon, F., Culp‐Hill, R., D' Alessandro, A., Kellems, R. E., Yoo, S.‐H., Han, L., Xia, Y. Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality. FASEB J. 33, 10528–10537 (2019). www.fasebj.org