2024 article
Myeloid cell-specific HMGB1 deficiency exaggerates mucoinflammatory response in Scnn1b-Tg+ mice
Mao, Y., Patial, S., & Saini, Y. (2024, November).
open access via doi.org (repository)
<title>Abstract</title> High mobility group box 1 (HMGB1), a highly conserved nuclear protein, is released into the extracellular milieu serving as a modulator of inflammatory responses. HMGB1 levels are elevated in the airspaces of CF patients and cystic fibrosis mice models. Previously, in an attempt to diminish BALF HMGB1 levels and modulate inflammatory outcomes in airspaces, we employed airway epithelial cell-specific HMGB1 deficient <italic>Scnn1b</italic>-Tg+ (Tg+) mice, a model of human cystic fibrosis (CF)-like lung diseases. While the deletion of airway epithelial cell-specific HMGB1 did not reduce BALF HMGB1 levels, the intracellular HMGB1 deficiency resulted in exaggerated inflammatory responses. In this study, because HMGB1 protein levels were found significantly elevated in Tg + BALF cells, we hypothesized that myeloid cell-derived HMGB1 deficiency will reduce BALF HMGB1 levels, which will modulate features of lung disease in Tg + mice. Accordingly, we introduced myeloid cell-specific HMGB1 deletion in Tg + mice. The deletion of HMGB1 in BALF myeloid cells did not result in any obvious alterations in the lungs of WT mice. As expected, HMGB1-sufficient Tg + mice displayed increased total cell counts consisting of neutrophils, eosinophils, and lymphocytes. As compared with the HMGB1-sufficient Tg + mice, the myeloid cell-specific HMGB1-deficient Tg + mice exhibited significantly increased BALF neutrophils and eosinophil counts, which was associated with increased BALF levels of granulocytes-specific chemoattractant, i.e., KC/CXCL1, MCP-1/CCL2, MIP-1α/CCL3, and MIP-1β/CCL4, Th2 lymphocyte-specific chemoattractant, i.e., TARC/CCL17 and MDC/CCL22, and monocyte chemoattractant, i.e., MCP-3/CCL7 and MCP-5/CCL12. As compared with the HMGB1-sufficient Tg + mice, the alveolar macrophages from HMGB1-deficient Tg + mice were significantly enlarged, suggesting their higher activation status. Myeloid cell-specific HMGB1 deletion also resulted in significantly improved clearance of spontaneous bacterial infection in Tg + mice. Furthermore, myeloid cell-specific HMGB1 deletion significantly worsened pathological manifestations in Tg + mice, i.e., exaggerated airway mucus obstruction, increased peribronchiolar infiltration of inflammatory cells, enlarged alveolar size, and increased lymphoid hyperplasia. Taken together, our data indicate that HMGB1 expression in myeloid cells modulates pathological features of mucoinflammatory lung disease in mice.