Abstract
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.
Highlights
The primary benefit derived from the host inflammatory response to infection is the potential eradication or containment of invading microbes
The major new findings of the current study were: 1) that monocyte chemotactic protein-inducible protein 1 (MCPIP1) expression in myeloid cells plays a central role in protecting against LPS-induced inflammation, lung injury and death; 2) that decreases in the MCPIP1 levels in macrophages following LPS inoculation are attributable, at least in part, to increased proteolysis by MALT1; 3) that pharmacologic inhibition of MALT1 with MI-2 protects against LPS-induced lung injury; 4) that both C/ EBPβ and C/EBPδ mRNAs are targets of MCPIP1 RNase; and 5) that the severe inflammatory syndrome that develops in mice with a global MCPIP1 deficiency is significantly delayed and has decreased severity in mice with a myeloid-specific MCPIP1 deficiency
We demonstrated that inflammatory damage to the lungs and that the protein and mRNA levels of various proinflammatory cytokines were elevated in the serum and lungs, respectively, of LPS-treated myeloid-specific MCPIP1 knockout mice compared to LPS treated control mice
Summary
The primary benefit derived from the host inflammatory response to infection is the potential eradication or containment of invading microbes. The host inflammatory response is mediated by cytokines, and their production is precisely regulated to permit rapid, robust responses to invading microbes, along with attenuation of those responses once the threat has been contained.[9,10] Lipopolysaccharide (LPS) is a component of the outer membrane of Gramnegative bacteria; it is among the most potent triggers of host inflammatory responses, and LPS-induced cytokine production is regulated at both the transcriptional and post-transcriptional levels. Transcription of cytokine genes is controlled by the following three transcription factors: NF-κB, C/EBPδ and ATF-3. ATF-3 subsequently suppresses C/EBPδ transcription, by which it suppresses the inflammatory response.[11,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
