Assistant Research Professor University of Connecticut Storrs, Connecticut, United States
Disclosure(s):
Arlind Mara, MS PhD: No financial relationships to disclose
Introduction/Rationale: Neutrophils are frontline effectors in bacterial pneumonia, providing rapid phagocytosis, degranulation, and NET formation to control pathogens, yet persistent or dysregulated neutrophil activity drives tissue injury and worsens outcomes. We recently showed neutrophils to be maladaptive during Mycoplasma infection while B cells appeared to modulate neutrophil dynamics through an unknown mechanism.
Methods: We combined targeted B cell depletion, passive transfers, high-parameter flow cytometry, and mixed-bone marrow chimera mice to assess the mechanisms by which B cells regulate neutrophilic inflammation during Mycoplasma infection. Outcome measures included neutrophil counts, Fas expression and apoptotic status, B cell localization and FasL expression, bacterial burden and histopathology.
Results: Passive transfer of hyperimmune serum failed to alter neutrophilia, lung pathology or pathogen load in Mycoplasma infected mice, implicating an antibody-independent regulatory mechanism. B cell depletion reproduced exacerbated neutrophilia. CXCL13-deficient bone marrow chimera mice, which lack luminal B cell recruitment to airway, but not to lung interstitium, exhibited exacerbated neutrophilia similar to B-cell depleted mice, supporting a contact-dependent regulatory mechanism. Screening of death receptors identified the Fas-FasL axis as the likely pathway for B-cell mediated killing of neutrophils. ~21% of luminal B cells expressed FasL, and ~73.6% of Fas+ neutrophils were found to be pre-apoptotic.
Conclusion: Altogether, these data define a previously undescribed Fas-FasL dependent mechanism by which airway recruited B cells regulate neutrophilic inflammation in the lung, highlighting cellular targets for immunomodulatory intervention in neutrophil-driven respiratory disease.
