Pathogenic role for CD101-negative neutrophils in the type I interferon-mediated immunopathogenesis of tuberculosis

  • Cell Rep. 2024 Dec 17;44(1):115072. doi: 10.1016/j.celrep.2024.115072.
Mohd Saqib  1 ,  Shreya Das  1 ,  Tanvir N Nafiz  1 ,  Elizabeth McDonough  2 ,  Poornima Sankar  1 ,  Lokesh K Mishra  1 ,  Ximeng Zhang  3 ,  Yi Cai  3 ,  Selvakumar Subbian  4 ,  Bibhuti B Mishra  5
Affiliations
  • 1. Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
  • 2. GE Healthcare Technology and Innovation Center, GE Research, Niskayuna, NY, USA.
  • 3. Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China.
  • 4. Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ, USA.
  • 5. Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA. Electronic address: [email protected].
PMID: 39693225 DOI: 10.1016/j.celrep.2024.115072
Abstract

Neutrophils are vital for immunity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), yet their heterogeneous nature suggests a complex role in TB pathogenesis. Here, we identify two distinct neutrophil populations based on CD101 expression, highlighting their divergent roles in TB. CD101-negative (CD101-ve) neutrophils, which resemble immature, pro-inflammatory granulocytes, exhibit reduced Mtb phagocytosis compared to their mature, CD101-positive (CD101+ve) counterparts. Our findings reveal that type I interferons (IFN-Is) suppress neutrophil Mtb uptake and drive the recruitment of CD101-ve neutrophils to the lungs. Infiltration of these cells promotes Mtb extracellular persistence, exacerbates epithelial damage, and impairs surfactant production. Furthermore, we demonstrate that granulocyte colony-stimulating factor (G-CSF) and Chemokine Receptor CXCR2 are essential for the pulmonary accumulation of CD101-ve neutrophils. Our study uncovers a pathogenic role for CD101-ve neutrophils in TB and highlights the IFN-I-dependent recruitment of this functionally compromised immature neutrophil as a driver of TB immunopathogenesis.

Keywords
CP: Immunology; CP: Microbiology; G-CSF; chemokine receptors; extracellular Mycobacterium tuberculosis; host-directed therapy; low-density neutrophils; lung epithelial cells; neutrophil mobilization; neutrophil subsets; tissue damage; type I interferon.
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