Systemic mast cell degranulation increases
mortality during polymicrobial septic
peritonitis in mice
Eric J. Seeley, Rachel E. Sutherland, Sophia S. Kim, and Paul J. Wolters1
Department of Medicine and The Cardiovascular Research Institute, University of California, San Francisco, California, USA
RECEIVED SEPTEMBER 27, 2010; REVISED APRIL 28, 2011; ACCEPTED MAY 13, 2011. DOI: 10.1189/jlb.0910531
MCs are required for an effective host response during
septic peritonitis. Local MC degranulation facilitates
neutrophil recruitment, activation, and bacterial killing.
However, the role of MCs located distant from the site
of infection is unknown. We studied the temporal and
spacial degranulation of MCs following CLP-induced
septic peritonitis. The functional importance of systemic
MC degranulation during infection was evaluated by
compartment-specific MC reconstitution. Serum hista-
mine, reflecting MC degranulation, was elevated 4 h af-
ter onset of septic peritonitis. Histologic examination
revealed progressive MC degranulation in select tis-
sues during the first 24 h of infection. MC-deficient Wsh
mice, reconstituted only in the peritoneal compartment,
had improved survival after CLP compared with con-
trols. However, reconstitution in peritoneal plus sys-
temic compartments worsened survival after CLP. IL-6
contributed to the detrimental effects of systemic MCs
on survival, as mice systemically reconstituted with
IL-6?/?MCs were more likely to survive than control
mice. These results indicate that in contrast to the ben-
efits of local MC activation during infection, systemic
MC activation worsens survival during CLP-induced
sepsis. J. Leukoc. Biol. 90: 591–597; 2011.
Sepsis is a complex syndrome with a high mortality [1, 2]. The
temporal importance of different molecular and cellular com-
ponents of the immune response during sepsis remains poorly
defined. There is mounting evidence that immune mecha-
nisms required for the initiation of host defense against local
infections may also contribute to multisystem organ injury and
death . MCs are key early initiators of the immune re-
sponse to infection [4, 5]. They line interfaces between the
host and the environment, including the epidermis and lumi-
nal surfaces of the airways and gut. MCs improve survival dur-
ing experimental mouse sepsis by secreting TNF, tryptase ,
and IL-6, which recruit and activate bactericidal neutrophils
[4, 5]. MCs also improve survival during sepsis by degrading
shock-promoting peptides, including endothelin-1  and
neurotensin . In contrast, other studies show that some MC-
derived products negatively affect survival during infection.
For example, mice lacking dipeptidyl peptidase I  or IL-15
only in MCs  have improved survival during infection.
Thus, MCs produce mediators that can improve or worsen sur-
vival after severe bacterial infections.
The importance of MCs at the site of bacterial infection is
well established [4, 5, 11]. However, it is not known if MCs
distant from the site of infection contribute to the host re-
sponse during sepsis. To define the response of systemic MCs
during infection, MC degranulation was evaluated by measur-
ing serum histamine and examining histologic sections during
CLP-induced sepsis. In addition, the contribution of systemic
MC degranulation to circulating inflammatory cytokines was
assessed using MC-deficient mice and cromolyn, a MC stabi-
lizer. Lastly, to test the importance of local and systemic MCs
during infection, MC-deficient Wsh mice were selectively re-
constituted with BMMCs in the local or the local plus the sys-
temic compartments and studied using the CLP model of
MATERIALS AND METHODS
All chemicals were from Sigma-Aldrich (St. Louis, MO, USA) unless noted
C57BL/6 IL-6?/?(WT) and C57BL/6 IL-6?/?mice were purchased from
The Jackson Laboratory (Bar Harbor, ME, USA). C57BL/6 Wsh mice 
were initially provided by Peter Besmer (Memorial Sloan-Kettering Insti-
tute, New York, NY, USA). Compared with control mice, C57BL/6 Wsh
mice have a severe reduction in total MC number. Eight-week-old Wsh mice
have a 90% reduction in tissue MCs compared with controls, and MCs are
undetectable in 10- to 12-week-old Wsh mice [13, 14]. All experimental pro-
cedures were performed on 8- to 12-week-old mice, and protocols were ap-
1. Correspondence: University of California, San Francisco, Box 0111, San
Francisco, CA 94143-0111. E-mail: firstname.lastname@example.org
Abbreviations: BM?bone marrow, CLP?cecal ligation and puncture, MC?
mast cell, rm?recombinant mouse, SCF?stem cell factor, s.d.?subdermally,
Brief Conclusive Report
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Volume 90, September 2011
Journal of Leukocyte Biology 591
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IL-6 ? innate immunity ? TLR4 ? infection
Seeley et al.
Systemic MC activation in sepsis
Volume 90, September 2011
Journal of Leukocyte Biology 597