Myeloid‐cell‐specific Ablation of Tristetraprolin (TTP) Increases the Susceptibility of Female mice to Bleomycin‐induced Lung Injury and Fibrosis

Abstract

Introduction Fibrotic interstitial lung diseases, including idiopathic lung fibrosis, are more prevalent and have poor prognosis in human males. Consistently, male mice are also more susceptible to the bleomycin-induced lung fibrosis. However, the underlying mechanisms for these gender/sex-associated differences in the development and presentation of these lung diseases remain unknown. Hypothesis Tristetraprolin (TTP), an RNA binding protein is an endogenous “off switch” of inflammation that functions by decreasing the mRNA stability of inflammatory mediators. Here, we tested the hypothesis that TTP is differentially expressed in male and female myeloid cells which results in differential sex-specific susceptibility to fibrotic lung diseases. Methods Eight to twelve-week old C57BL/6 wild type (WT), TTP myeloid cell-specific knockout (TTPmyeKO; LysMCre/Cre/TTPflox/flox, and flox-only control (TTPflox/flox; LysMWT/WT/TTPflox/flox) mice were exposed to bleomycin. Lung injury, inflammation, and fibrosis was assessed at days 14, 21, and 28. Results As compared to WT male mice, WT female mice manifested significantly decreased cellular infiltration and lung injury at day 14. Interestingly, female myeloid cells expressed significantly higher levels of TTP compared to male mice at day 14. In contrast to TTPflox/flox mice, TTPmyeKO male as well as female mice exhibited an exaggerated response to bleomycin, including leucocytic infiltration, lung injury, and fibrosis. Conclusions These findings suggest that myeloid-TTP expression exhibits sex-specificity and that myeloid-TTP is a critical factor that determines the susceptibility to fibrotic interstitial lung disease. Impact Our findings emphasize the importance of myeloid cells and their genetic repertoire as a contributor to gender/sex-specific differences in the susceptibility to idiopathic pulmonary fibrosis.