Bacterial Clearance and Survival Are Dependent on CXC Chemokine Receptor-2 Ligands in a Murine Model of Pulmonary Nocardia asteroides Infection

Abstract

Survival from murine pulmonary nocardiosis is highly dependent on CXC chemokine receptor-2 (CXCR2) ligand-mediated neutrophil chemotaxis and subsequent clearance of the infectious agent Nocardia asteroides. Intratracheal inoculation of N. asteroides rapidly up-regulated the CXC chemokines macrophage inflammatory protein-2 (MIP-2) and KC within 24 h, with levels remaining elevated through day 3 before returning to near baseline levels by day 7. Coinciding with elevated MIP-2 and KC were the rapid recruitment of neutrophils and clearance of the organism. Anti-Ly-6G Ab-mediated neutrophil depletion before bacterial challenge resulted in strikingly increased mortality to N. asteroides infection. The relative contribution of MIP-2 in neutrophil recruitment was examined by anti-MIP-2 Ab treatment before nocardial infection. MIP-2 neutralization had no detrimental effects on survival, neutrophil recruitment, or bacterial clearance, suggesting the usage of additional or alternative CXCR2-binding ligands. The importance of the CXC family of chemokines was determined by the administration of an anti-CXCR2 Ab capable of blocking ligand binding in vivo. Anti-CXCR2 treatment greatly increased mortality by preventing neutrophil migration into the lung. Paralleling this impaired neutrophil recruitment was a 100-fold increase in lung bacterial burden. Combined, these observations indicate a critical role for neutrophils and CXC chemokines during nocardial pneumonia. These data directly link CXCR2 ligands and neutrophil recruitment and lend further support to the concept of CXC chemokine redundancy. For infections highly dependent on neutrophils, such as nocardial pneumonia, this is of critical importance.

Anti-Fas Induces Hepatic Chemokines and Promotes Inflammation by an NF-κB-independent, Caspase-3-dependent Pathway

“…There is some evidence that KC and MIP-2 differ as neutrophil chemoattractants in vivo (38,39). For example, although KC and MIP-2 are both induced in the lung in response to Nocardia asteroides infection (40) and bleomycin treatment (41), neutralizing antibodies against MIP-2 have little effect on tissue inflammation. This parallels exactly what we found with MIP-2 neutralization in liver.…”

Resident Cell Chemokine Expression Serves as the Major Mechanism for Leukocyte Recruitment During Local Inflammation

“…The role of CXCR2 in neutrophil recruitment has been consistently reported (5)(6)(7)(8)(9)(10)(11)(12), but the role of CCR1 remains controversial. Although CCR1 or MIP-1␣ deficiency has been shown to inhibit neutrophil migration in some models (13,14,16), a lack of effect has been reported in other studies (7,44).…”

“…The exudates were collected 4 h after challenge, processed, and analyzed as described. This treatment has been shown to deplete neutrophils in a variety of bacterial and fungal provocation models in vivo (8,32,33).…”

Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target?

“…CXC chemokine secretion can be triggered through recognition of bacterial endotoxin. 22,23 CXC chemokines are also produced in response to apoptosis or cell damage. 24 Bacterial endotoxin leakage from the gastrointestinal (GI), a consequence of conditioning regimens, 11 is considered a GVHD trigger.…”