Blockage of Lamin-A/C loss diminishes the pro-inflammatory macrophage response
Preprint posted on 22 February 2022 https://www.biorxiv.org/content/10.1101/2022.02.22.481454v1
Article now published in iScience at http://dx.doi.org/10.1016/j.isci.2022.105528
Categories: biochemistry, cell biology, immunology
Background. Nuclei of mammalian cells are delimited by a lipid bilayer contiguous to the endoplasmic reticulum and are surrounded by several types of filamentous proteins, which together form the nuclear envelope. The major components of the nuclear envelope are proteins termed Lamins, located at the inner nuclear membrane, and associated to several other factors to control nuclear integrity, mechanics, chromatin organization and gene expression (Ho and Lammerding, 2012). Lamins defects are associated with pathological conditions termed laminopathies, which interestingly show an augmented inflammatory cellular phenotype (Tran et al., 2016). However, the relationship between Lamins and inflammation is not well defined. Whether and how Lamins play a role in immune cell activation, particularly macrophage activation, is the focus of the following preprint.
Key findings of this preprint
1) LPS treatment diminishes Lamin-A/C levels in macrophages. Starting from publicly available datasets, the authors found that in several in vivo and in vitro models of lipopolysaccharide (LPS)-treated macrophages, the Lamin-A/C transcript is consistent downregulated. To better refine this phenomenon and understand the underlying mechanism, they recapitulated the observation using bone marrow derived macrophages (BMDM). They confirmed the Lmna gene is gradually switched off and the LMNA protein levels decrease upon LPS treatment.
2) Lamin-A/C is phosphorylated and degraded upon macrophage activation. During mitosis, Lamin-A/C dissolution is preceded by CDK1 phosphorylation and Caspase-6-mediated fragmentation. Consistently with this model of disassembly, in immunoblot experiments, Lamin-A/C was found to be phosphorylated between 3 to 6 hours post LPS administration. Later, both fragmentation and degradation were observed, peaking at 24h after LPS treatment. Pharmacological modulation of CDK1 and Caspase-6 activity, coupled with experiments in a Lamin-A/C knock-out BMDM model, confirmed that the same pathways responsible for Lamin disassembly during mitosis are also involved in Lamin-A/C reduction upon macrophage activation.
3) Cytokines and type-I interferon are upregulated alongside Lamin-A/C reduction. Using bulk RNA-seq from WT and Lamin-A/C KO BMDM either at rest or after 6 h of LPS treatment, the authors observed a higher inflammatory and type-I interferon (IFN-I) phenotype in KO macrophages and a downregulation of genes related to DNA damage repair already at steady state. Genes further upregulated by LPS administration belonged to inflammatory and IFN-I signature, underlining an increased IFN-I-STAT1 signaling along Lamin-A/C downregulation. A further suggestion that IFN-I may primes Lamin-A/C KO BMDM to an increased inflammatory response upon LPS activation was obtained by treating them with selective inhibitors of the JAK-STAT pathway, which diminished the activation phenotype upon LPS administration.
4) Lamin-A/C control of inflammatory phenotype also occurs during bacterial infection. To corroborate this novel finding and to extend it to a more general paradigm, the final experiments provided by the authors aimed to probe the overall mechanism in a model of bacterial infection. Indeed, E. coli infection recapitulated the same phenotype of Lamin-A/C reduction previously observed with purified LPS. Importantly, pharmacological inhibition of Lamin-A/C phosphorylation reduced the inflammatory response to bacterial infection, thus suggesting a potential future therapeutical exploitation of this pathway to modulate excessive or pathologic macrophage-driven inflammation.
In summary, the authors uncover a new link beetwen lamin-A/C dynamics and macrophage activation; which provide a re-thinking of inflammation and how it could be modulated for therapeutic purposes.
Why I chose this preprint
I found this work to be a nice example of mechanistic insight into a molecular process relevant to a complex cellular phenotype, namely macrophage activation. The data and observations made by the authors are extremely interesting, and they were able to connect and further expand different unanswered questions with relatively simple and clever experimental approaches.
Questions to the authors
- RAW264.7 macrophages were suggested not being suitable to recapitulate primary macrophage signaling and functional processes. Are THP-1 or other cell lines generally thought to be reliable to study macrophage activation and signaling?
- Do other forms of activation, like IFN-I administration to culture medium, reduce Lamin-A/C levels in macrophages?
- Is LaminB1 also downregulated during macrophage activation?
References
- C. Y. Ho, J. Lammerding, Lamins at a glance. J. Cell Sci. 125, 2087–2093 (2012)
- J. R. Tran, H. Chen, X. Zheng, Y. Zheng, Lamin in inflammation and aging. Curr. Opin. Cell Biol. 40 (2016)
Posted on: 5 April 2022 , updated on: 6 April 2022
doi: https://doi.org/10.1242/prelights.31721
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