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 mice with cystic fibrosis (CF)--like lung disease. To reduce extracellular release of HMGB1 into the lung airspaces, we previously introduced airway epithelial cell-specific HMGB1 deficiency in Scnn1b -Tg+ (Tg+) mice, a model of human CF-like lung disease. While the deletion of airway epithelial cell-specific HMGB1 did not reduce bronchoalveolar lavage fluid (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 extracellular HMGB1 levels in the lung airspaces of Tg+ mice, which will modulate pathological features of lung disease in Tg+ mice. Accordingly, we introduced myeloid cell-specific HMGB1 deficiency in Tg+ mice. The deletion of HMGB1 in myeloid cells did not result in any obvious alterations in the lungs of WT mice. The BALF levels of HMGB1 were comparable between myeloid cell-specific HMGB1-deficient Tg+ and HMGB1-sufficient Tg+ mice. As expected, as compared with the HMGB1-sufficient WT, 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 neutrophil and eosinophil counts, which was associated with increased BALF levels of granulocyte-specific chemoattractants, i.e., KC/CXCL1, MCP-1/CCL2, MIP-1α/CCL3, and MIP-1β/CCL4, Th2 lymphocyte-specific chemoattractants, i.e., TARC/CCL17 and MDC/CCL22, and monocyte-specific chemoattractants, 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, increased alveolar space enlargement, and increased lymphoid hyperplasia. Collectively, although myeloid cells are not the source of extracellular HMGB1 found in the inflamed airspaces of Tg+ mice, the myeloid cell-specific HMGB1 deficiency modulates key pathological features of mucoinflammatory lung disease in these mice.
Mao et al. (Mon,) studied this question.