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TNFAIP3 Reduction-of-Function Drives Female Infertility and CNS Inflammation


Women with autoimmune and inflammatory aetiologies can exhibit reduced fecundity. TNFAIP3 is a master negative regulator of inflammation, and has been linked to many inflammatory conditions by genome wide associations studies, however its role in fertility remains unknown. Here we show that mice harbouring a mild Tnfaip3 reduction-of-function coding variant (Tnfaip3 (I325N)) that reduces the threshold for inflammatory NF-kappaB activation, exhibit reduced fecundity. Sub-fertility in Tnfaip3 (I325N) mice is associated with irregular estrous cycling, low numbers of ovarian secondary follicles, impaired mammary gland development and insulin resistance. These pathological features are associated with infertility in human subjects. Transplantation of Tnfaip3 (I325N) ovaries, mammary glands or pancreatic islets into wild-type recipients rescued estrous cycling, mammary branching and hyperinsulinemia respectively, pointing towards a cell-extrinsic hormonal mechanism. Examination of hypothalamic brain sections revealed increased levels of microglial activation with reduced levels of luteinizing hormone. TNFAIP3 coding variants may offer one contributing mechanism for the cause of sub-fertility observed across otherwise healthy populations as well as for the wide variety of auto-inflammatory conditions to which TNFAIP3 is associated. Further, TNFAIP3 represents a molecular mechanism that links heightened immunity with neuronal inflammatory homeostasis. These data also highlight that tuning-up immunity with TNFAIP3 comes with the potentially evolutionary significant trade-off of reduced fertility.

Type Journal
ISBN 1664-3224 (Electronic) 1664-3224 (Linking)
Authors Zammit, N. W.; McDowell, J.; Warren, J.; Muskovic, W.; Gamble, J.; Shi, Y. C.; Kaczorowski, D.; Chan, C. L.; Powell, J.; Ormandy, C.; Brown, D.; Oakes, S. R.; Grey, S. T.
Publisher Name Frontiers in Immunology
Published Date 2022-04-30
Published Volume 13
Published Pages 811525
Status Published in-print
DOI 10.3389/fimmu.2022.811525
URL link to publisher's version