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SENP1 Promotes Caspase-11 Inflammasome Activation and Aggravates Inflammatory Response in Murine Acute Lung Injury
Mingjun Du1, Wenhan Wang2, Shaoyuan Zhang3
1Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China.
Background:
Infection is the leading cause of acute lung injury (ALI). Macrophages, which are pivotal innate immune cells, play a critical role in mediating inflammatory processes. Intracellular lipopolysaccharide (LPS) from invasive Gram-negative bacteria can activate the caspase-11 inflammasome, leading to the induction of pyroptosis in macrophages. This process subsequently triggers the release of inflammatory cytokines and damage-associated molecular patterns from pyroptotic macrophages, thereby exacerbating inflammatory progression in ALI. However, the precise regulatory mechanisms governing caspase-11 activation is still unclear. Sentrin-specific proteases (SENPs) have been identified as notable targets for their anti-inflammatory properties. Nevertheless, the specific role of SENPs in macrophage pyroptosis during the pathogenesis of ALI remains unknown.
Methods:
We used LPS as an endotoxin to induce ALI. We analyzed the expression and location of sentrin-specific protease 1 (SENP1), pulmonary impairment, macrophage infiltration, caspase-11 inflammasome expression and activation, caspase-11 SUMOylation, and inflammatory cytokine secretion.
Results:
Upregulated expression of SENP1 in lung tissue and macrophages was observed following LPS stimulation. SENP1 mediates de-SUMOylation and activation of caspase-11 inflammasome in macrophages. Moreover, pharmacological inhibition or genetic deficiency of SENP1 in macrophages significantly improved ALI-related histological damage by reducing the secretion of inflammatory cytokines and suppressing caspase-11-dependent pyroptosis.
Conclusions:
Collectively, our findings highlight the involvement of SENP1 in caspase-11 activation and inflammatory progression in macrophages, thereby establishing a scientific foundation for the exploration of novel therapeutic strategies aimed at treating ALI.
