Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

Abstract

Gamma interferon (IFN-␥) is an important driver of intestinal inflammation during colitis caused by Salmonella enterica serovar Typhimurium. Here we used the mouse colitis model to investigate the cellular sources of IFN-␥ in the cecal mucosa during the acute phase of an S. Typhimurium infection. While IFN-␥ staining was detected in T cells, NK cells, and inflammatory monocytes at 2 days after infection, the majority of IFN-␥-positive cells in the cecal mucosa were neutrophils. Furthermore, neutrophil depletion blunted mucosal Ifng expression and reduced the severity of intestinal lesions during S. Typhimurium infection. We conclude that neutrophils are a prominent cellular source of IFN-␥ during the innate phase of S. Typhimurium-induced colitis. Individuals with primary immunodeficiencies impairing production of gamma interferon (IFN-␥) or IFN-␥ signaling present in childhood with disseminated bacterial infections. The vast majority of these infections are caused by two bacterial pathogens: nontyphoidal Salmonella serovars and weakly virulent Mycobacterium species (1). Nontyphoidal Salmonella serovars, such as S. enterica serovar Typhimurium, cause a localized gastroenteritis in immunocompetent individuals, which is characterized by acute intestinal inflammation and diarrhea (reviewed in references 2 and 3). The importance of innate immune responses during gastroenteritis is illustrated by the rapid onset of intestinal inflammation, which gives rise to symptoms within 24 h of ingesting S. Typhimurium (4). A histopathological hallmark of S. Typhimurium-induced gastroenteritis is a severe acute infiltrate of neutrophils in the ileal and colonic mucosae (5, 6). Studies using a mouse model of S. Typhimurium-induced colitis show that in animals lacking IFN-␥, the severity of intestinal inflammation is markedly attenuated (7,8).Conventional wisdom holds that IFN-␥ is produced during the innate phase of a bacterial infection by natural killer (NK) cells and NKT cells (reviewed in reference 9) while CD4 ϩ and CD8 ϩ T cells become the principal cellular sources at later stages, which are governed by adaptive immune responses (reviewed in references 10 and 11). Consistent with this idea, splenic NK cells are a prominent cellular source of innate IFN-␥ production in models of systemic S. Typhimurium infection (12-14). Furthermore, CD1D-restricted NKT cells contribute to innate IFN-␥ production in the livers and spleens of mice with disseminated S. Typhimurium infection (15, 16). However, the identities of the innate immune cells contributing to early IFN-␥ production in the intestinal mucosa have not been fully resolved. The goal of this study was to identify the cellular sources of innate IFN-␥ production in the intestinal mucosa during S. Typhimurium-induced colitis. MATERIALS AND METHODSBacterial strains and culture conditions. S. Typhimurium strain IR715 is a fully virulent, nalidixic acid-resistant derivative of wild-type isolate ATCC 14028 (American Type Culture Collection) (17). Bacteria were cultured overnight ae...

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