Ubiquitination was recently identified as a central process in the pathogenesis and development of numerous inflammatory diseases, such as obesity, atherosclerosis, and asthma. Treatment with proteasomal inhibitors led to severe side effects because ubiquitination is heavily involved in a plethora of cellular functions. Thus, new players regulating ubiquitination processes must be identified to improve therapies for inflammatory diseases. In addition to their role in adaptive immunity, endosomal MHC class II (MHCII) molecules were shown to modulate innate immune responses by fine tuning the TLR4 signaling pathway. However, the role of MHCII ubiquitination by membrane associated ring-CH-type finger 1 (MARCH1) E3 ubiquitin ligase in this process remains to be assessed. In this article, we demonstrate that MARCH1 is a key inhibitor of innate inflammation in response to bacterial endotoxins. The higher mortality of March1 mice challenged with a lethal dose of LPS was associated with significantly stronger systemic production of proinflammatory cytokines and splenic NK cell activation; however, we did not find evidence that MARCH1 modulates LPS or IL-10 signaling pathways. Instead, the mechanism by which MARCH1 protects against endotoxic shock rests on its capacity to promote the transition of monocytes from Ly6C to Ly6C Moreover, in competitive bone marrow chimeras, March1 monocytes and polymorphonuclear neutrophils outcompeted wild-type cells with regard to bone marrow egress and homing to peripheral organs. We conclude that MARCH1 exerts MHCII-independent effects that regulate the innate arm of immunity. Thus, MARCH1 might represent a potential new target for emerging therapies based on ubiquitination reactions in inflammatory diseases.
Membrane-associated RING-CH-1 (March1) is a member of the March family of E3 ubiquitin ligases. March1 downregulates cell surface expression of MHC II and CD86 by targeting them to lysosomal degradation. Given the key roles of MHC class II and CD86 in T cell activation and to get further insights into the development of allergic inflammation, we asked whether March1 deficiency exacerbates or attenuates features of allergic asthma in mice. Herein, we used an acute model of allergy to compare the asthmatic phenotype of March1-deficient and -sufficient mice immunized with ovalbumin (OVA) and later challenged by intranasal instillation of OVA in the lungs. We found that eosinophilic inflammation in airways and lung tissue was similar between WT and March1−/− allergic mice, whereas neutrophilic inflammation was significant only in March1−/− mice. Airway hyperresponsiveness as well as levels of IFN-γ, IL-13, IL-6, and IL-10 was lower in the lungs of asthmatic March1−/− mice compared to WT, whereas lung levels of TNF-α, IL-4, and IL-5 were not significantly different. Interestingly, in the serum, levels of total and ova-specific IgE were reduced in March1-deficient mice as compared to WT mice. Taken together, our results demonstrate a role of March1 E3 ubiquitin ligase in modulating allergic responses.
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Aim: Polarization of macrophages to M1 or M2 phenotypes will dictate the effectiveness of host responses against specific infections. Membrane-associated RING-CH (MARCH1) has been shown to be implicated in the activation of antigen presenting cells and is readily induced by the anti-inflammatory cytokine IL-10. Here, we set out to investigate the role of MARCH1 in the activation of macrophages and its implication in host responses. Results: We show that MARCH1-deficient bone-marrow-derived macrophages exhibit a bias toward M1 polarization as assessed by quantitative real-time PCR, cytometric bead array (CBA) and flow cytometry. Furthermore, a macrophage population showing intermediate surface markers (CD11bint and F4/80int) between M1 and M2 was observed in the peritoneal cavity of MARCH1-deficient mice. In addition, these mice were found to be more susceptible to LPS-induced shock and exhibited higher pro-inflammatory cytokine production in their serum as monitored by CBA. Finally, MARCH1-deficient mice showed an enhanced clearing of leishmania parasites in the spleen at 21 and 28 days post infection. Conclusion: These results show that MARCH1 contributes to the polarization and functional plasticity of macrophages. Conflict of Interest disclosure: No conflict to declare.
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