Neutrophil serine proteases (NSPs; elastase, cathepsin G, and proteinase-3) directly kill invading microbes. However, excess NSPs in the lungs play a central role in the pathology of inflammatory pulmonary disease. We show that serpinb1, an efficient inhibitor of the three NSPs, preserves cell and molecular components responsible for host defense against Pseudomonas aeruginosa . On infection, wild-type (WT) and serpinb1 -deficient mice mount similar early responses, including robust production of cytokines and chemokines, recruitment of neutrophils, and initial containment of bacteria. However, serpinb1 −/− mice have considerably increased mortality relative to WT mice in association with late-onset failed bacterial clearance. We found that serpinb1 -deficient neutrophils recruited to the lungs have an intrinsic defect in survival accompanied by release of neutrophil protease activity, sustained inflammatory cytokine production, and proteolysis of the collectin surfactant protein–D (SP-D). Coadministration of recombinant SERPINB1 with the P. aeruginosa inoculum normalized bacterial clearance in serpinb1 −/− mice. Thus, regulation of pulmonary innate immunity by serpinb1 is nonredundant and is required to protect two key components, the neutrophil and SP-D, from NSP damage during the host response to infection.

We studied the role of CD43 (leukosialin/sialophorin), the negatively charged sialoglycoprotein of leukocytes, in the binding of mycobacteria to host cells. CD43-transfected HeLa cells bound Mycobacterium avium , but not Salmonella typhimurium or Shigella flexneri . Quantitative bacteriology showed that macrophages (Mφ) from wild-type mice (CD43 +/+ ) bound M . avium , Mycobacterium bovis (bacillus Calmette-Guérin), and Mycobacterium tuberculosis (strain H37Rv), whereas Mφ from CD43 knockout mice (CD43 −/ −) did not. Fluorescence microscopy demonstrated that the associated M . avium had been ingested by the CD43 +/+ Mφ. The inability of CD43 −/ − Mφ to bind M . avium could be restored by addition of galactoglycoprotein (Galgp), the extracellular mucin portion of CD43. The effect of Galgp is not due to opsonization of the bacteria, but required its interaction with the Mφ; other mucins had no effect. CD43 expression by the Mφ was also required for optimal induction by M . avium of tumor necrosis factor (TNF)-α production, which likewise could be reconstituted by Galgp. In contrast, interleukin (IL)-10 production by M . avium– infected Mφ was CD43 independent, demonstrating discordant regulation of TNF-α and IL-10. These findings describe a novel role of CD43 in promoting stable interaction of mycobacteria with receptors on the Mφ enabling the cells to respond specifically with TNF-α production.