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.