# The protective role of MDL-1 in sepsis-induced lung injury: insights from a murine CLP model

## TL;DR

This study shows that MDL-1 helps protect against lung damage in sepsis by reducing harmful inflammation in mice.

## Contribution

The study reveals that MDL-1 deficiency worsens sepsis-induced lung injury through increased inflammation and altered cytokine profiles.

## Key findings

- MDL-1-deficient mice had a 42.9% 7-day survival rate in sepsis, significantly lower than wild-type mice.
- Lung injury scores were higher in MDL-1-deficient mice, with increased IL-6 and TNF-α and decreased IFN-γ.
- Phospho-Syk and cleaved caspase-3 levels were elevated in MDL-1-deficient septic mice, indicating heightened inflammation.

## Abstract

The Myeloid DAP12-associating lectin-1 (MDL-1) serves as a pivotal pattern recognition receptor crucial for recognizing various pathogenic microorganisms and orchestrating immune responses during infections. This study aimed to elucidate the role of MDL-1 in the pathogenesis of sepsis-associated acute lung injury (ALI).

Experiments were conducted using wild-type (WT) and MDL-1-deficient (MDL-1-/-) mice on a C57BL/6 background. Sepsis was induced by cecal ligation and puncture (CLP) surgery, with sham-operated mice serving as controls. Lung tissues were harvested 24 hours post-CLP for histopathological evaluation using hematoxylin and eosin (H&E) staining. MDL-1 expression on monocytes/macrophages was analyzed by flow cytometry. Cytokines of IFN-γ, IL-6, and TNF-α were measured via ELISA. Protein expression was assessed by western blot, and mRNA levels of key cytokines and chemokines in lung tissues were quantified using real-time PCR.

Survival analysis revealed that MDL-1 deficiency significantly exacerbated mortality in septic mice. In the CLP-induced sepsis model, the 7-day survival rate was 78.6% in the WT-CLP group, whereas it was markedly reduced to 42.9% in the MDL-1-/--CLP group, demonstrating a statistically significant difference between the groups (P < 0.01). Histopathological assessment further confirmed that lung tissue damage was more severe in MDL-1-/--CLP mice compared to their WT-CLP counterparts, as evidenced by a significantly higher composite injury score. MDL-1 expression was markedly upregulated on monocytes and macrophages (P < 0.01). Serum IL-6 and TNF-α levels were significantly elevated, whereas IFN-γ was reduced (P < 0.01). mRNA expression of cytokines and chemokines was correspondingly altered (P < 0.01). Furthermore, protein levels of phospho-Syk (p-Syk) and cleaved caspase-3 in lung tissues were significantly increased (P < 0.01).

Our findings demonstrate that MDL-1 deficiency exacerbates lung inflammation in a CLP-induced murine sepsis model. These results underscore the essential immunomodulatory role of MDL-1 in mitigating excessive pulmonary inflammatory responses during sepsis.

The Myeloid DAP12-associating lectin-1 (MDL-1) serves as a pivotal pattern recognition receptor crucial for recognizing various pathogenic microorganisms and orchestrating immune responses during infections. In this study, we elucidate that MDL-1 exhibits predominant expression within the mononuclear phagocyte system and plays a significant role in modulating the severity of lung injury in sepsis. Notably, MDL-1-deficient (MDL-1-/-) mice subjected to cecal ligation and puncture (CLP) exhibited elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α, along with decreased production of IFN-γ. Moreover, the expression levels of chemokines like IP-10, KC, MCP-1, and MIP-1 were markedly upregulated in septic MDL-1-/- mice. Concurrently, enhanced levels of Syk and cleaved caspase 3 were detected in the lung tissues of MDL-1-/--CLP animals, underscoring an augmented inflammatory response. Collectively, our findings indicate that MDL-1 deficiency correlates with the exacerbation of lung inflammation in a murine model of CLP-induced sepsis, highlighting the critical immunomodulatory role of MDL-1 in safeguarding against excessive pulmonary inflammation.