Resumen de Lamin A/C as a modulator of myeloid immune responses in viral infections and inflammatory bowel disease
A-type lamins (lamin A/C) are type V intermediate filament proteins that form the nuclear lamina (NL) along with B-type lamins. NL is in the internal part of the inner nuclear membrane and interacts with chromatin, transcription factors, and nuclear pore complexes. Lamin A/C regulates many functions, highlighting its fundamental role in the maintenance of nuclear architecture and mechanical stability. Dendritic cells (DCs) are a complex myeloid subset that bridges innate and adaptive immune responses by acting as professional antigen presenting cells. Using a mouse model lacking lamin A/C (Lmna-/-) specifically in the myeloid compartment, we studied the role of lamin A/C in DCs. GM-CSF Lmna-/--bone marrow-derived DCs (BMDCs), differentiated in vitro, showed a diminished capacity to form conjugates with naïve CD4+ T cells and to promote CD4+ T cell activation and proliferation when matured with Lipopolysaccharide (LPS). However, the opposite results were obtained when the cells were kept in an immature state. Lamin A/C deficiency in mature DCs alters NF-κB nucleus-cytoplasm localization and NF-κB-dependent transcription. Additionally, Lmna-/--BMDCs showed lower expression of proinflammatory genes without an apparent effect on the expression of MHC-II and other co-stimulatory molecules. In vivo, LysM-Cre Lmna-/- mice generated lower Th1 and CTL responses and less viral clearance upon Vaccinia virus infection compared to WT, when the virus was administered intraperitoneally or by skin scarification in the tail. However, when subcutaneous infection was performed, differences were observed between genotypes only at 6 days post-infection, but not at 14 days after. These results suggest that lamin A/C modulates myeloid response to Vaccinia virus, depending on the route of infection. On the other hand, when young and adult mice were infected with Influenza A virus, differences in symptomatology and weight loss between WT and LysM-Cre Lmna-/- mice were only notable in adult mice. The observed results can be explained by the fact that lamin A/C deficiency in myeloid cells leads to the loss of monocytic alveolar macrophages in the lungs. Furthermore, the absence of lamin A/C in some myeloid populations protects against the development of inflammatory bowel disease in mice as they presented a milder disease, showing less weight loss, less symptomatology, and less shortening of the colon compared to their WT counterparts. A model of colitis based on dextran sodium sulfate (DSS) administration was used. With therapeutic interest, the adoptive transfer of immature Lmna-/--BMDCs to WT mice before DSS treatment, improved colitis by reducing the percentage of IFNγ+ CD8+ T cells and increasing the proportion of Treg cells. Here, we demonstrated that the action of lamin A/C is context-dependent, modulating myeloid cell plasticity and function. This work lays the groundwork to enhance immunotherapies based on DCs or developing new therapeutics to treat infectious or inflammatory diseases
