TGFbeta receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis.
In bacterial meningitis, chemokines lead to recruitment of polymorphonuclear leucocytes (PMN) into the CNS. At the site of infection in the subarachnoid space, PMN release reactive oxygen species, reactive nitrogen intermediates (RNI) and interleukin-1beta (IL-1beta). Although these immune factors assist in clearance of bacteria, they also result in neuronal injury associated with meningitis. Transforming growth factor beta (TGFbeta) is a potent deactivator of PMN and macrophages since TGFbeta suppresses the production of ROI, RNI and IL-1. Here, we report that the deletion of the TGFbeta receptor II gene in PMN enhances PMN recruitment into the CNS of mice with Streptococcus pneumoniae meningitis. This was associated with more efficient clearance of bacteria, and almost complete prevention of intracerebral necrotizing vasculitis. Differences in PMN in the CNS of infected control mice and mice lacking TGFbeta receptor II were not explained by altered expression of chemokines acting on PMN. Instead, TGFbeta was found to impair the expression of L (leucocyte)-selectin on PMN from control mice but not from mice lacking TGFbeta receptor II. L-selectin is known to be essential for PMN recruitment in bacterial meningitis. We conclude that defective TGFbeta signalling in PMN is beneficial in bacterial meningitis by ameliorating migration of PMN and bacterial clearance.
Malipiero
Ursula
U
Clinical Immunology, University Hospital Zurich, Zurich, Switzerland.
Koedel
Uwe
U
Pfister
Hans-Walter
HW
Levéen
Per
P
Bürki
Kurt
K
Reith
Walter
W
Fontana
Adriano
A
D000818:Animals; D002543:Cerebral Hemorrhage / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D017353:Gene Deletion; D007113:Immunity, Innate / Q000276:immunology; D019041:L-Selectin / Q000032:analysis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008586:Meningitis, Pneumococcal / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D010586:Phagocytes / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020293:Vasculitis, Central Nervous System / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control
D018125:Receptors, Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin