TitleCentral role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury.
Publication TypeJournal Article
Year of Publication2017
AuthorsLi, Yong, Huang Xuan, Huang Shengping, He Hui, Lei Tianhua, Saaoud Fatma, Yu Xiao-Qiang, Melnick Ari, Kumar Anil, Papasian Christopher J., Fan Daping, and Fu Mingui
JournalSignal Transduct Target Ther
Date Published2017

<p>Although systemic inflammatory responses attributable to infection may lead to significant lung injury, the precise molecular mechanisms leading to lung damage are poorly understood and therapeutic options remain limited. Here, we show that myeloid monocyte chemotactic protein-inducible protein 1 (MCPIP1) plays a central role in protecting against LPS-induced inflammation and lung injury. Myeloid-specific MCPIP1 knockout mice developed spontaneous inflammatory syndromes, but at a late age compared to global MCPIP1 knockout mice. Moreover, mice with a myeloid-specific deletion of MCPIP1 were extremely sensitive to LPS-induced lung injury due to overproduction of proinflammatory cytokines and chemokines. We identified C/EBPβ and C/EBPδ, two critical transcriptional factors that drive cytokine production and lung injury, as targets of MCPIP1 RNase. LPS administration caused MCPIP1 protein degradation in the lungs. Pharmacological inhibition of MALT1, a paracaspase that cleaves MCPIP1, by MI-2 selectively increased the MCPIP1 protein levels in macrophages and in the lungs. Meanwhile, administration of MI-2 protected mice from LPS-induced inflammation, lung injury and death. Collectively, these results indicate that myeloid MCPIP1 is central in controlling LPS-induced inflammation and lung injury. Pharmacological inhibition of MALT1 protease activity may be a good strategy to treat inflammatory diseases by enhancing MCPIP1 expression in myeloid cells.</p>

Alternate JournalSignal Transduct Target Ther
PubMed ID29263935
PubMed Central IDPMC5721545
Grant ListP01 AT003961 / AT / NCCIH NIH HHS / United States
R01 HL116626 / HL / NHLBI NIH HHS / United States
R21 AI103618 / AI / NIAID NIH HHS / United States