Abstract
The pleiotropic Src kinase Lyn has critical roles in host defense in alveolar macrophages against bacterial infection, but the underlying mechanism for Lyn-mediated inflammatory response remains largely elusive. Using mouse Pseudomonas aeruginosa infection models, we observed that Lyn−/− mice manifest severe lung injury and enhanced inflammatory responses, compared with wild-type littermates. We demonstrate that Lyn exerts this immune function through interaction with IL-6 receptor and cytoskeletal protein Ezrin via its SH2 and SH3 domains. Depletion of Lyn results in excessive STAT3 activation, and enhanced the Src homology 2-containing inositol-5-phopsphatase 1 (SHIP-1) expression. Deletion of SHIP-1 in Lyn−/− mice (double knockout) promotes mouse survival and reduces inflammatory responses during P. aeruginosa infection, revealing the rescue of the deadly infectious phenotype in Lyn deficiency. Mechanistically, loss of SHIP-1 reduces NF-κB-dependent cytokine production and dampens MAP kinase activation through a TLR4-independent PI3K/Akt pathway. These findings reveal Lyn as a regulator for host immune response against P. aeruginosa infection through SHIP-1 and IL-6/STAT3 signaling pathway in alveolar macrophages.
Highlights
Pseudomonas aeruginosa is an opportunistic bacterium causing acute and chronic infection in immunocompromised people,[1] such as patients with cystic fibrosis, chronic obstructive pulmonary disease, severe burns and cancer
We demonstrate that Lyn directly binds to interleukin-6 receptor (IL-6R) to regulate IL-6/STAT3 signaling pathway in alveolar macrophages (AMs)
Lyn − / − mice show increased inflammatory responses and severe lung injury following PAO1 infection To investigate the physiological relevance of Lyn in P. aeruginosa infection, we intranasally instilled laboratory strain PAO1 at 1 × 107 clonal-forming units (CFU) for each Lyn− / − mouse (Supplementary Figure 1A) as well as WT control mouse to establish an acute pneumonia model and compared the survival the expression of other inflammatory factors,[36] we studied rates of these two groups of mice (10 mice per group)
Summary
Pseudomonas aeruginosa is an opportunistic bacterium causing acute and chronic infection in immunocompromised people,[1] such as patients with cystic fibrosis, chronic obstructive pulmonary disease, severe burns and cancer. Previous reports from us and others showed that Lyn is located on the inner leaflet of the plasma membrane and in the proximity of lipid rafts, and can be translocated into the activated membrane domains to transmit cellular signals for either facilitating phagocytosis or regulating inflammatory responses.[17,18,19] Upon Klebsiella pneumoniae infection, Lyn negatively regulates inflammatory responses via the p38/NF-κB signaling pathway to maintain a balanced inflammation.[20] Lyn is critical for P. aeruginosa internalization into lung cells.[21] Lyn is activated to be associated with lipid rafts and TLR2, playing an important role in the initial stages of. During P. aeruginosa infection, SHIP-1 positively regulates NF-κB signaling pathway, but negatively regulates MAPK signaling pathway through Akt activation These results provide new insight into the function of Lyn in bacterial infection. Two hours before PAO1 infection as indicated, MH-S cells were treated with 20 μM STAT3 inhibitor VI (Merck Millipore, Bellerica, MA, USA), NF-κB inhibitor
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